Systems, methods and devices for maintenance, guidance and/or control

ABSTRACT

Methods, systems, devices and computer program products for providing maintenance, guidance and/or control of certain systems are disclosed. Typically, in some aspects the systems are complex. Also disclosed are methods, systems, devices and computer program products for providing therapeutic guidance for controlling a subject&#39;s circulation. One such method comprises the steps of: (i) determining the subject&#39;s present and desired circulatory states as a function of at least mean systemic filling pressure (P ms ), heart efficiency (E H ) and systemic vascular resistance (SVR); (ii) determining a target direction of a trajectory from the subject&#39;s present circulatory state to said subject&#39;s desired circulatory state, wherein treatment of the subject so as to traverse the trajectory will cause the subject&#39;s circulatory state to move towards a desired circulatory state; and (iii) visually representing the target direction of the trajectory.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is related to U.S. Provisional Application filed onJan. 31, 2008, Ser. No. 61/006,790, entitled “SYSTEMS, METHODS, ANDDEVICES, FOR MAINTENANCE, GUIDANCE AND CONTROL” and U.S. ProvisionalApplication filed on Feb. 5, 2008, Ser. No. 61/006,895, entitled“SYSTEMS, METHODS, AND DEVICES, FOR MAINTENANCE, GUIDANCE AND CONTROL”both of which are herein incorporated by reference in their entirety.

FIELD OF THE DISCLOSURE

This disclosure relates to systems, methods and devices for maintenance,guidance and/or control of certain systems. In certain aspects, thisdisclosure relates to systems, methods and devices for therapeuticmaintenance, guidance and/or control of mammalian circulation usingmeasurement, interpretation, and/or therapy.

BACKGROUND

External monitoring and control of the certain complex systems is animportant yet complex and difficult problem in many situations. Forexample, external monitoring and control of the circulation is animportant yet complex and difficult problem in humans and other mammals,particularly in acutely disordered and severely diseased states. It isone of the most commonly performed tasks in human and veterinaryintensive care units and other areas of critical care includinganesthesia and emergency care. The task involves the measurement ofvariables relating to the circulation including blood pressures, bloodflows (cardiac output), heart rate, and oxygen levels. In currentclinical practice, a physician (or veterinarian) or nurse interprets themeasured data and applies various diagnostic and therapeuticinterventions. Typical therapies include infusion of volume (e.g., inthe form of normal saline), diuretics, vasoconstrictors andvasodilators, and medications that affect the strength, rhythm orrelaxation of the heart. One of the aims of this clinical task is tomaintain the circulatory state at a desired level. This desired level isusually articulated in the patient record, but not always consistently.The purpose of the desired state is to ensure adequate blood and oxygenperfusion to vital tissues and removal of metabolic products.

Current circulatory management relies primarily on the education,training and experience of the bedside clinician team, which in practicehas produced high variability in approaches and results. A commonconcept is that of pre-load. One definition of pre-load in cardiacphysiology is the pressure stretching the ventricle of the heart, afterpassive filling and atrial contraction. If the chamber is not mentioned,it is usually assumed to be the left ventricle. For example, if thepre-load is low, then an increase of circulating blood volume may beindicated (by increased administration of normal saline or volumeexpander). Unfortunately, pre-load is a qualitative concept and not aquantitative measure and there are numerous different definitions ofpre-load.

Some intensive care units are beginning to introduce paper protocols forcirculatory management. However, the most common practice is that ofindividual interpretation of the varying monitored data and judgment ontherapy change.

A number of problems arise from current practice. A wide variety ofcircumstances including acute subject problems, complexity, clinicalinexperience, lack of vigilance and confusion over the desired state canresult in the circulation entering areas compromising a subject'swellbeing. This may require extra clinical effort, medications and timeto return the circulation to a more desirable state. Furthermore, theperturbed state may itself entail side effects, for example, atrialfibrillation in an overpowered circulation and/or shock and organfailure if pressures and flows are insufficient. These side effectsincrease morbidity, prolong time in intensive care, increase the risk ofdeath and add considerably to the costs of care.

A need therefore exists to provide methods, systems and/or devices forimproving guidance and/or control in certain systems such as complexsystems. A need also exists to improve the clinical process of improvingcirculatory guidance and/or control of unstable circulations in warmblooded animals and provide related methods, systems and/or devices. Aneed also exists to improve the critical care clinical process ofmonitoring, treating, and/or improving circulatory guidance and/orcontrol of unstable circulations in warm blooded animals and providerelated methods, systems and/or devices. A need also exists to providemethods, systems and/or devices for improving circulatory guidanceand/or control in subjects, thereby reducing, among other things, thehazard associated with side effects. A need also exists to improve theclinical process of improving circulatory guidance and/or control bysystematizing the care of unstable circulations and/or supporting a teamapproach to such care. The present disclosure provides variouscombinations of systems, methods, and/or devices for the care, theguidance and/or the control of certain types of systems. Certainembodiments may also produce better end results for the systems.

SUMMARY

Certain embodiments relate to systems, methods and devices formaintenance, guidance and/or control of certain systems for use incritical care. For example, many critically ill and high-risk patientsadmitted to intensive care, or in other settings, require circulatoryintervention or support. In certain embodiments, the delivery ofcirculatory support often involves selecting at least certainhemodynamic values to target and deciding which interventions should beused to move towards and/or achieve desired endpoints or targets. Incertain embodiments, interventions for circulatory state management canbe to some extent classified into at least three types: fluid therapyfor control, or substantial control, of volume state; therapies toimprove heart performance such as inotropes, heart rate and rhythminterventions; and vasoactive therapies (dilators and constrictors).Optimal application of these therapies in critically ill and high-riskpatients is surprisingly lacking in the art.

Clinical data to support circulatory intervention to achieve variousexplicitly stated haemodynamic targets in a number of settings, such asseptic shock and high-risk operative patients are known. However,translation of these recommendations into clinical practice is oftensubjective in practice and presents numerous challenges to the staffproviding circulatory intervention. Frequently circulatory control isneeded for 24 hours per day and sometimes for weeks or other extendedtime periods. While specific setting of objective targets may occur theuse of different interventions by various staff at various levels ofskill to achieve these targets often involves subjective decisionmaking. As disclosed herein, the task of achieving targeted circulatorysupport in shocked and high-risk patient groups is aided by acomputerised point of care guidance systems where guidance is determinedat least in part by objective rules that are physiologically based andcontinually adapt to the patient's state. Certain embodiments disclosedherein provide a computerized circulatory guidance system that is aflexible platform to assist the delivery of circulatory interventions toachieve explicit targets. Certain disclosed embodiments provide systems,methods and devices that acquires haemodynamic data from the bedsidemonitor and graphically represents physician determined explicit targetsin relation to present patient measured variables. In certainembodiments the haemodynamic data is acquired automatically. Both thepatient's position and the targets may be displayed visually, forexample, on volumetric, resistance and heart performance axes and aguidance arrow continually indicates which next therapy (i.e.volumetric, vasoactive/resistive or cardioactive) will take the patienttoward the desired blood pressure, cardiac output and oxygen deliverytargets.

Certain embodiments relate to systems, methods, devices and computerprogram products for providing maintenance, guidance and/or control ofcertain complex systems.

Certain embodiments relate to systems, methods and devices fortherapeutic maintenance, guidance and/or control of mammaliancirculation using measurement, interpretation and/or therapy. Certainembodiments relate to computer-assisted methods for therapeutic guidancefor controlling a subject's circulation. Exemplary subjects that may besuitable include a range of patients with unstable circulationspresenting to the ICU critical care units, operating rooms, anesthesia,high dependency care, emergency rooms, trauma and field medicine, withexemplary conditions including, for example, pre & post open heartsurgery, pre & post major surgery, septic shock, renal failure, majorburns, major trauma, cardiogenic shock or combinations thereof.

Certain embodiments may also produce better end results for the systems.In some embodiments, better end results may include improved circulatorycontrol in which blood pressure, cardiac output and/or oxygen deliveryare controlled, or substantially controlled, to desired values.

For example, circulatory targets could be varied to those moreappropriate to the patient, as judged from the system, and these targetsacquired faster and more accurately. By providing better care monitoringand/or guidance certain embodiments will produce better end results (orsubstantially better end results), less side effects (or substantiallyless side effects), more efficient care guidance (or substantially moreefficient care guidance) and/or more efficient treatment (orsubstantially more efficient treatment) of the patient. Some examples ofbetter clinical end results are increased survival, reduced length ofstay and increased functioning following hospital discharge. Using theembodiments disclosed herein the average care giver (or a range caregivers with vary levels of stall) is able to acquire the desiredcirculatory target at least as fast as, or substantial as fast, as anexpert physician who is dedicated to the task of monitoring the patient.Using certain embodiments disclosed herein a range of care givers withvarious levels of experience are able to acquired the desiredcirculatory target 5%, 10%, 15%, 20%, 25% or 30% faster then the samecare givers would achieve without such a monitoring system. In addition,in many situations the guidance given as to how to acquire the desiredtarget will produce better end results (or substantially better endresults), less side effects (or substantially less side effects), moreefficient care guidance (or substantially more efficient care guidance),and/or more efficient treatment (or substantially more efficienttreatment) of the patient. In addition, the disclosed embodimentsprovide a regular monitoring of the patients state and allow forfrequent adjustments to the patient based on how that patients statusevolves. Using certain embodiments disclosed it is possible to monitorand assess the circulatory state of a patient at frequent time intervals(for example, every 2, 5, 10, 20, 30 seconds, 1, 2, 3, 5, 10, 20, 30minutes or other desired periods of time 24 hours a day for an extendedperiod of time). Certain embodiments disclosed provide for an improvedand/or more detailed assessment of a patient's continually evolvingcirculatory state and response to treatment. Using certain disclosedsystems results in many situations in a more cost effective treatment ofthe patient.

Using certain disclosed embodiments to achieve circulatory goals in agroup of patients undergoing recovery from high risk surgery and/orshock will yield reduction in complications and/or decrease in ICU timeand/or decrease in mortality and/or decrease in cost. Using certaindisclosed embodiments to achieve circulatory goals in at least onepatient undergoing recovery from high risk surgery and/or shock yieldsreductions in complications, decreased ICU time, decreased mortalityand/or decreased cost.

One exemplary consequence of improved circulatory control is thereduction of side effects, for example, fluid overload; dehydration,pulmonary edema, atrial fibrillation and/or organ failure. These sideeffects are often the result of poor calibration and choice of therapy,such as IV saline, diuretics, pressors, etc. Frequently, the patient'scirculatory system behaves in a counter-intuitive manner which resultsin poor therapy choices. One example would be when the patient'scirculatory is under powered (i.e., low MAP and CO), fluid therapy maynot always result in improved MAP and CO. Certain embodiments disclosedherein may reduce the frequency of this type of situation and the sideeffects which arise. A further consequence of the side effects is theneed for additional therapy and time in intensive care to correct forthe side effect. Not only does this discomfort the patient and exposethem to the risk of long-term side effects, it substantially increasesthe cost of care.

Certain embodiments relate to systems and/or methods used to representthe subject's determined and/or present and desired circulatory statesas a function of at least mean systemic filling pressure, heartefficiency and systemic vascular resistance as a on-screen, audio ordata print-out representation.

Certain embodiments relate to systems and/or methods used to representthe subject's circulatory state and the subject's desired circulatorystate as a function of mean systemic filling pressure, heart efficiency,systemic vascular resistance or combinations thereof. In certainaspects, these states will be represented in a two-dimensional graphicalformat. In certain embodiments, these states will be represented inthree-dimensional and other graphical formats, such as bar chart orradial charts. In certain embodiments, representing the subject'scirculatory state may often be accomplished by use of visual and/oraudio means or combinations thereof.

Certain embodiments relate to systems and/or methods that may be used todetermine a target direction and trajectory from the subject's presentcirculatory state to the subject's desired circulatory state on thetwo-dimensional, three-dimensional or other form of representation,wherein treatment of the subject so as to traverse said trajectory willcause the subject's mean arterial pressure (MAP) and cardiac output(CO)/oxygen delivery to converge to and/or move towards the subject'sdesired circulatory state. In certain embodiments, where the subject'soxygen saturation and hemoglobin levels are known, controlling thecardiac output will also cause the subject's oxygen delivery or venousoxygen to converge to a desired state. Said trajectory consists of thechanges required in the individual treatments for volume, resistance andheart efficiency and the sequence of treatments needed.

Certain embodiments relate to systems and/or methods to visuallyrepresenting the subject's actual and desired circulatory states as afunction of mean systemic filling pressure, heart efficiency, andsystemic vascular resistance as a two-dimensional representation anddetermining a target direction of a trajectory from the subject's actualcirculatory state to the subject's desired circulatory state on thetwo-dimensional representation, wherein treatment of the subject so asto traverse said trajectory will cause the subject's mean arterialpressure (MAP) and cardiac output (CO) to converge to, and/or movetowards, the subject's desired circulatory state.

Certain embodiments are to computer-assisted methods, systems and/ordevices for assessing a subject's circulation state, comprising at leastone of the following steps: (i) determining said subject's presentcirculatory state using parameters sufficient to characterize thepresent circulatory state; and (ii) determining said subject's desiredcirculatory state using parameters sufficient to characterize thedesired circulatory state. In certain aspects, the methods, systemsand/or devices may be used for providing a treatment guidance for asubject. In certain aspects, the methods, systems and/or devices areused to measure the subjects circulation state. In certain aspects, atarget direction is determined of a trajectory from the subject'spresent circulatory state to said subject's desired circulatory state.In certain aspects, where treatment guidance is desirable, the targetdirection and the trajectory are used to assisted in moving thesubject's circulatory state along towards a desired circulatory state.In certain aspects, where treatment guidance is desirable, the targetdirection and the trajectory are used to assisted in providing treatmentsequencing guidance in order to move said subject's circulatory statealong towards a desired circulatory state. In certain aspects, thesubject's present circulatory state is determined as a function of atleast mean systemic filling pressure (P_(ms)), heart efficiency (E_(H))and systemic vascular resistance (SVR). In certain aspects, thesubject's desired circulatory state is determined as a function of atleast mean systemic filling pressure (P_(ms)), heart efficiency (E_(H))and systemic vascular resistance (SVR). In certain aspects, the subjectspresent circulatory state is continually determined. In certain aspects,the methods, systems and/or devices provide substantially continuousand/or intermittent guidance of said subjects circulatory state, and/orcontrol of hemodynamic and oxygen management of the subject'scirculatory system. In certain aspects, the methods, systems and/ordevices provide substantially continuous and/or intermittent guidance ofthe subjects circulatory state, and/or control of hemodynamic and oxygenmanagement of said subject's circulatory system. In certain embodiments,the methods, systems and/or devices provide substantially continuousand/or intermittent guidance of at least one of the following: fluidtherapies for control of volume state, heart performance therapy, heartrate therapies, heart rhythm therapies and/or vasoactive therapies.

Various parameters may be used to characterize the subject's circulatorystate. Various combinations of parameters may be used with certaindisclosed embodiments. For example, in certain embodiments, at leastMAP, RAP and CO are used to determine at least P_(ms), E_(H) and SVR.Other combinations of parameters and/or therapeutic targets arecontemplated. For example, certain embodiments may target at leastOxygen delivery, as a function of at least CO. Certain embodiments maydetermine P_(ms) from other combinations of variables. For example, RAPmay be replaced by a measurement of venous pressure at a peripherallocation. The MAP and CO terms may be replaced by a function of thearterial pressure waveform measured at a variety of locations. Thepatient's gender and other demographic variables may be used to derivevariants to determine P_(ms). When a known volume of fluid isadministered, the change in P_(ms), however determined, may be used toestimate the patient's systemic vascular compliance, which can providemethods for additional circulatory assessment and/or guidance. Analternate form of volume state measure other than P_(ms) is the stressedvascular volume, which is Pms divided by the vascular compliance. Otherembodiments provide for the circulation targets to be time varying.Other embodiments provide for targeting of derived variables, forexample to keep SVR within a defined range or to keep Pms within adefined range.

Certain embodiments are to computer-assisted methods, systems and/ordevices for assessing a subject's circulation state, comprising at leastone of the following steps: (i) means for determining said subject'spresent circulatory state using parameters sufficient to characterizethe present circulatory state; and (ii) means for determining saidsubject's desired circulatory state using parameters sufficient tocharacterize the desired circulatory state. In certain aspects, a meansfor determining a target direction of a trajectory from the subject'spresent circulatory state to said subject's desired circulatory state.In certain aspects, where treatment guidance is desirable, the targetdirection and the trajectory are used to assisted in providing a meansfor treatment sequencing guidance in order to move said subject'scirculatory state along towards a desired circulatory state. In certainaspects, means for determining the subject's present circulatory stateas a function of at least mean systemic filling pressure (P_(ms)), heartefficiency (E_(H)) and systemic vascular resistance (SVR).

Certain embodiments are to computer-assisted methods, systems and/ordevices for providing therapeutic guidance of a subject's circulatorystate, said method comprising the steps of: (i) determining saidsubject's present and desired circulatory states as a function of atleast mean systemic filling pressure (P_(ms)), heart efficiency (E_(H))and systemic vascular resistance (SVR); (ii) determining a targetdirection of a trajectory from said subject's present circulatory stateto said subject's desired circulatory state, wherein treatment of saidsubject so as to traverse said trajectory will cause said subject'scirculatory state to move towards a desired circulatory state; and (iii)visually representing the target direction of said trajectory to assistin the treatment. In certain aspects, a treatment sequencing guidance isprovided. In certain aspects, steps (i) to (iii) are performedrepeatedly based on updated values of said subject's present and/ordesired state. In certain aspects, the treatment of the subject so as totraverse the trajectory will cause the subject's mean arterial pressure(MAP) and cardiac output (CO) to converge to the subject's desiredcirculatory state. In certain embodiments, the methods, systems and/ordevices provide for substantially continuous. In certain embodiments,the methods, systems and/or devices provide for intermittent guidance.In certain embodiments, substantially continuous and/or intermittentguidance of the subjects circulatory state and/or control of hemodynamicand oxygen management of the subject's circulatory system is provided.In certain embodiments, substantially continuous and/or intermittentguidance of at least one of the following: fluid therapies for controlof volume state, heart performance therapy, heart rate therapies, heartrhythm therapies and/or vasoactive therapies is provided.

Certain embodiments disclose a computer program product comprising acomputer readable medium comprising a computer program recorded thereinfor assessing a subject's circulation state, said method comprising,said computer program product comprising: (i) computer program codemeans for assisting in the determination of said subject's presentcirculatory state using parameters sufficient to characterize thepresent circulatory state; (ii) computer program code means forassisting in the determination of said subject's desired circulatorystate using parameters sufficient to characterize the desiredcirculatory state; (iii) computer program code means for visuallyrepresenting said subject's present and desired circulatory states; (iv)computer program code means for determining a target direction of atrajectory from said subject's present circulatory state to saidsubject's desired circulatory state, wherein treatment of said subjectso as to traverse said trajectory will cause said subject's meanarterial pressure (MAP) and cardiac output (CO) to converge to saidsubject's desired circulatory state; and (v) computer program code meansfor visually representing the target direction of said trajectory. Incertain aspects, the computer program product further comprisingcomputer program code means for executing said computer program codemeans (i) to (v) repeatedly based on updated values of said subject'spresent and/or desired state. In certain aspects, the computer programproduct provides computer program code means for determining atrajectory comprising: (vi) computer program code means for projectingMAP and CO isograms of said subject's present mean arterial pressure(MAP) and present cardiac output (CO) on said visual representation;(vii) computer program code means for bisecting an inner angle subtendedby intersecting MAP and CO isograms, said inner angle in the quadrantthe desired patient state is in; and (viii) computer program code meansfor selecting the bisection of said inner angle as the target directionof said trajectory. In certain aspects, the computer program productprovides for computer program code means for visually representing atarget range for the subject's MAP and CO. In certain aspects, thecomputer program product further comprises computer program code meansfor controlling an infusion rate of a medication administered to thesubject in accordance with the trajectory.

Certain embodiments provide a circulatory monitoring and guidancesystem, comprising: a data acquisition unit; a visual display unit; amemory unit for storing data and instructions to be performed by aprocessing unit; and a processing unit coupled to said data acquisitionunit, said visual display unit and said memory unit, said processingunit programmed to: (i) obtain subject specific parameters based onanthropometric data; (ii) acquire measured values of variables relatingto said subject's circulation via said data acquisition unit; (iii)compute values of mean systemic filling pressure (P_(ms)), heartefficiency (E_(H)) and systemic vascular resistance (SVR) for saidsubject based on said subject specific parameters and said measuredvalues; (iv) visually display said subject's present and desiredcirculatory states as a function of mean systemic filling pressure(P_(ms)), heart efficiency (E_(H)) and systemic vascular resistance(SVR) on said visual display unit; (v) determine a target direction of atrajectory from said subject's actual circulatory state to saidsubject's desired circulatory state, wherein treatment of said subjectso as to traverse said trajectory will cause said subject's meanarterial pressure (MAP) and cardiac output (CO) to converge to saidsubject's desired circulatory state; and (vi) visually display thetarget direction of said trajectory on said visual display unit. Incertain aspects, the circulatory monitoring and guidance system theprocessing unit is programmed to execute steps (i) to (vi) repeatedlybased on updated values of the subject specific parameters and themeasured values. In certain aspects, the processing unit is programmedto represent systemic vascular resistance (SVR) as an abscissa, meansystemic filling pressure (P_(ms)) as a primary ordinate and heartefficiency (E_(H)) as a secondary ordinate on said two-dimensionalrepresentation. In certain aspects, the processing unit is programmed tocontrol an infusion rate of a medication administered to said subject inaccordance with said trajectory.

Certain embodiments disclose a computer-assisted method for assessing asubject's circulation state, the method comprising: (i) deriving atleast the subject's present mean systemic filling pressure (P_(ms)),heart efficiency (E_(H)) and systemic vascular resistance (SVR) frommeasurements of at least the subjects MAP, CO and RAP; (ii) deriving forthe subject at least targeted mean systemic filling pressure (P_(ms)),heart efficiency (E_(H)) and systemic vascular resistance (SVR) valuesfrom at least target values of MAP, CO and RAP; (iii) determining forthe subject a desired target direction of a trajectory from saidsubject's present state to said subject's desired state, whereintreatment of said subject so as to traverse said trajectory will causesaid subject's circulatory state to move towards a desired circulatorystate. In certain aspects, the computer-assisted method provides forsubstantially continuous and/or intermittent guidance and/or control ofhemodynamic and oxygen management of said subject's circulatory system.In certain aspects, the computer-assisted method is used for circulatorystate management. In certain aspects, the computer-assisted method isused to provide substantially continuous and/or intermittent guidance ofat least one of the following: fluid therapies for control of volumestate, heart performance therapy, heart rate therapies, heart rhythmtherapies and/or vasoactive therapies. In certain aspects, thecomputer-assisted method is used to determine therapeutic changes on acontinuous and/or intermittent guidance basis of at least one of thefollowing volume state, heart performance, heart rate, heart rhythmand/or constriction or dilation of blood vessels.

Certain embodiments provide systems, methods and/or devices that mayused in a closed loop control system, open loop control system, orcombinations thereof. Certain embodiments may be used in a closed loopcontrol system of intravenous and syringe pumps for volume, vasoactiveand/or heart treatments.

Certain embodiments related to systems and/or methods including meansfor representing the subject's determined and desired circulatory statesas a function of systemic filling pressure, heart efficiency andsystemic vascular resistance as a two-dimensional representation. Incertain embodiments, a minimal amount of information may be used todetermine circulatory states. For example, in certain embodiments, onlysystemic filling pressure and vascular resistance can be used. As willbe discussed in more detail below, this minimal information may incertain situations be less desirable since it may not allow fordistinguishing whether volume or cardiac treatment is needed. Thus incertain situations, a more desirable representation may include heartefficiency. In the case of the latter, we have later defined heartefficiency in terms of mean systemic filling pressure (Pms) and rightatrial pressure (RAP). There may be other forms of this function thatmay be used as well. Additional factors may also be included, forexample, but not limited to, the volume responsiveness parameters. Thegraphical display may be extended to include other variables such asheart rate or intracranial pressure. In certain embodiments, the displaymay depict isograms for the target MAP and CO ranges. The CO range mayalso be depicted as a cardiac index (CI) range or oxygen delivery (DO2I)range. Means for representing the subject's circulatory state may oftenbe accomplished by use of at least one visual, at least one audio orcombinations thereof.

Certain embodiments are to computer-assisted methods and/or systems forassessing a subject's volume responsiveness state, the methods and/orsystems comprising at least one of the following steps: (i) determiningthe subject's present volume responsiveness state as a function of atleast mean systemic filling pressure (P_(ms)) and heart efficiency(E_(H)); and (ii) determining the subject's desired volume responsivestate as a function of at least mean systemic filling pressure (P_(ms))and heart efficiency (E_(H)). In certain aspects, the computer assistedmethods and/or systems are used for providing a treatment guidance forthe subject. In certain aspects, the computer-assisted methods and/orsystems a target direction is determined of a trajectory from thesubject's present volume responsiveness state to the subject's desiredvolume responsiveness state. Certain embodiments are tocomputer-assisted methods and/or systems wherein the treatment guidance,the target direction and the trajectory are used to assist in providingtreatment sequencing guidance in order to move the subject's volumeresponsiveness state along towards a desired volume responsivenessstate. In certain embodiments, the subject's present state and/or thesubject's desired state are visually represented. In certain aspects,the computer-assisted methods and/or systems provide that the subjectspresent volume responsive state and/or the subjects desired volumeresponsiveness may be continually determined. In certain embodiments,the computer-assisted methods and/or systems provides substantiallycontinuous and/or intermittent guidance of the subjects volumeresponsive state.

Certain embodiments are to computer-assisted methods and/or systems forassessing at least one of a subject's power volume responsiveness andcardiac output volume responsiveness, said methods and/or systemscomprising: (i) determining at least one of said subject's present powervolume responsiveness and present cardiac output volume responsivenessusing parameters sufficient to characterize at least one of saidsubject's power volume responsiveness and cardiac output volumeresponsiveness; and (ii) determining at least one of said subject'sdesired power volume responsiveness and desired cardiac output volumeresponsiveness using parameters sufficient to characterize at least oneof said subject's power volume responsiveness and cardiac output volumeresponsiveness; wherein heart efficiency (E_(H)) is substantiallyconstant. In certain aspects, the computer assisted methods and/orsystems are used for providing a treatment guidance for said subject. Incertain aspects, the computer assisted methods and/or systems may beused to measure at least one of said subject's power volumeresponsiveness state and cardiac output volume responsiveness state. Incertain aspects, the computer-assisted methods and/or systems may beused wherein a target direction is determined of a trajectory from atleast one of said subject's present power volume responsiveness stateand present cardiac output volume responsiveness state to at least oneof said subject's desired power volume responsiveness state and desiredcardiac output volume responsiveness state. In certain embodiments, thecomputer-assisted methods and/or systems may be used wherein thetreatment guidance, the target direction and the trajectory are used toassisted in moving at least one of said subject's present power volumeresponsiveness state and present cardiac output volume responsivenessstate along towards at least one of a desired power volumeresponsiveness state and a desired cardiac output volume responsivenessstate. In certain embodiments, the computer-assisted methods and/orsystems may be used wherein the treatment guidance, the target directionand the trajectory are used to assisted in providing treatmentsequencing guidance in order to move at least one of said subject'spower volume responsiveness state and cardiac output volumeresponsiveness state along towards at least one of a desired powervolume responsiveness state and a desired cardiac output volumeresponsiveness state. In certain aspects, the computer-assisted methodsand/or systems provide that said subject's present state and/or saidsubject's desired state are visually represented. In certainembodiments, the computer-assisted methods and/or systems may be usedwherein at least one of said subjects present power volumeresponsiveness state and present cardiac output volume responsivenessstate and/or at least one of said subjects desired power volumeresponsiveness state and desired cardiac output volume responsivenessstate is continually determined. In certain embodiments, thecomputer-assisted methods and/or systems provides substantiallycontinuous and/or intermittent guidance of at least one of said subjectspower volume responsiveness state and present cardiac output volumeresponsiveness state.

Certain embodiments relate to systems and/or methods including means fordetermining a target direction of a trajectory from the subject'sdetermined circulatory state to the subject's desired circulatory stateon the two-dimensional representation, wherein treatment of the subjectso as to traverse said trajectory will cause the subject's mean arterialpressure (MAP) and cardiac output (CO)/oxygen delivery to converge to,and/or move towards, the subject's desired circulatory state.

Certain embodiments relate to systems and/or methods that include meansfor visually representing the subject's determined and desiredcirculatory states as a function of at least one mean systemic fillingpressure, at least one heart efficiency, and at least one systemicvascular resistance as a two-dimensional representation and means fordetermining a target direction of a trajectory from the subject's actualcirculatory state to the subject's desired circulatory state on thetwo-dimensional representation, wherein treatment of the subject so asto traverse said trajectory will cause the subject's mean arterialpressure (MAP) and cardiac output (CO)/oxygen delivery to converge to,and/or move towards, the subject's desired circulatory state.

Certain embodiments relate to systems, methods and devices fortherapeutic maintenance, guidance and/or control of mammaliancirculation using measurement, interpretation and/or therapy. Certainembodiments relate to computer-assisted methods for therapeutic guidancefor controlling a subject's circulation. The methods may includevisually representing the subject's actual and desired circulatorystates as a function of mean systemic filling pressure, heart efficiencyand systemic vascular resistance as a two-dimensional representation anddetermining a target direction of a trajectory from the subject's actualcirculatory state to the subject's desired circulatory state on thetwo-dimensional representation, wherein treatment of the subject so asto traverse said trajectory will cause the subject's mean arterialpressure (MAP) and cardiac output (CO) to converge to the subject'sdesired circulatory state. In certain aspects, the methods may furtherinclude visually representing the target direction of the trajectory onthe two-dimensional representation. Certain embodiments relate tocirculatory monitoring and guidance systems or devices that includes adata acquisition unit; a visual display unit; a memory unit for storingdata and instructions to be performed by a processing unit; and aprocessing unit coupled to the data acquisition unit, the visual displayunit and the memory unit. In some aspects, the processing unit may beprogrammed to obtain subject specific parameters based on anthropometricdata; acquire measured values of variables relating to the subject'scirculation via the data acquisition unit; compute values of meansystemic filling pressure, heart efficiency and systemic vascularresistance for the subject based on the subject specific parameters andthe measured values; visually display the subject's actual and desiredcirculatory states as a function of mean systemic filling pressure,heart efficiency and systemic vascular resistance on the visual displayunit; determine a target direction of a trajectory from the subject'sactual circulatory state to the subject's desired circulatory state,wherein treatment of the subject so as to traverse the trajectory willcause the subject's mean arterial pressure (MAP) and cardiac output (CO)to converge to the subject's desired circulatory state; and visuallydisplay the target direction of the trajectory on the visual displayunit.

In certain embodiments, the target direction of the trajectory may bevisually represented as an arrow. In certain aspects, the method and/ormethods may further include visually representing a target range for thesubject's MAP and CO on the two-dimensional representation.

In certain embodiments, the method and/or methods may further includecontrolling an infusion rate of a medication administered to the subjectin accordance with the trajectory.

BRIEF DESCRIPTION OF THE DRAWINGS

Features and advantages will become apparent from the followingdescription of embodiments thereof, by way of example only, withreference to the accompanying drawings, in which:

FIG. 1 is a 2-dimensional {P_(ms), SVR} graphical representation of the3-dimensional {P_(ms), E_(H), SVR} space in accordance with certainembodiments;

FIG. 2 shows MAP and CO isograms projected on the {P_(ms), SVR} space ofFIG. 1 in accordance with certain embodiments;

FIG. 3 shows geometrical determination of an optimal trajectory usingthe 2-dimensional {P_(ms), SVR} graphical representation of FIGS. 1 and2 in accordance with certain embodiments;

FIG. 4 is a logical block diagram of a circulatory monitoring andguidance system in accordance with certain embodiments;

FIG. 5 is a flowchart of method for controlling a computer system forperforming circulatory monitoring and guidance in accordance withcertain embodiments;

FIG. 6 is another 2-dimensional {P_(ms), SVR} graphical representationof the 3-dimensional {P_(ms), E_(H), SVR} space in accordance withcertain embodiments;

FIG. 7 is logical block diagram of another circulatory monitoring andguidance system in accordance with certain embodiments;

FIG. 8 is a schematic block diagram of a computer system in accordancewith certain embodiments of the inventions; and

FIGS. 9-18 are an exemplary method for operating a system or device inaccordance with certain embodiments;

FIGS. 19 a-19 c are exemplary representations of the 3-dimensional{P_(ms), E_(H), SVR} space in accordance with certain embodiments;

FIG. 20 is an exemplary algorithm for controlling a circulatory guidancesystem in accordance with certain embodiments;

FIG. 21 is an exemplary relational chart for E_(H) versus P_(ms) inaccordance with certain embodiments;

FIG. 22 is an exemplary relational chart for W versus P_(ms) inaccordance with certain embodiments;

FIGS. 23-29 are exemplary representations of the 3-dimensional {P_(ms),E_(H), SVR} space in accordance with certain examples provided herein;

FIG. 30 is an exemplary illustration of a standalone circulatoryguidance system in accordance with certain embodiments;

FIG. 31 is an exemplary illustration of a circulatory guidance systemcoupled to a bedside monitor and specialist cardiac monitor inaccordance with certain embodiments;

FIG. 32 is an exemplary illustration of a configuration of a visualdisplay of a circulatory guidance system in accordance with certainembodiments;

FIGS. 33 a-33 d are exemplary illustrations of various physicalarrangements of circulatory guidance systems and bedside monitors inaccordance with certain embodiments;

FIGS. 34-36 are exemplary illustrations for automated control systems(e.g., for i.v., blood pressure, and dialysis) and accordance withcertain exemplary embodiments;

FIG. 37 is an exemplary illustration of primary endpoint results; and

FIGS. 38-39 are charts comparing certain data results.

DETAILED DESCRIPTION

This disclosure relates generally to systems, methods, devices andcomputer program products for providing maintenance, guidance and/orcontrol of certain systems. Often these systems may be complex systems.Complex systems such as the cardiovascular system or the respiratorysystem provide data that is often hard to interpret properly in order todetermine the appropriate course of action or treatment in view of theinformation provided. For example, a subject with hypertension may betreated with anti-hypertensives as a first line therapy. If the subjectfails to respond, further observation and consideration may reveal thatthe subject is volume overloaded with a high cardiac output and thesystem may suggest the need to reduce volume state through diuresis.This action may reduce the blood pressure to normal levels.

In some aspects, this disclosure relates to, but is not limited to,systems, methods and devices for therapeutic maintenance, guidanceand/or control of mammalian circulation using measurement,interpretation and/or therapy. Certain embodiments relate tocomputer-assisted methods for therapeutic guidance for controlling asubject's circulation. This may be used in a number of situations andsettings such as hospitals, critical care units, general intensive careunits, surgical intensive care units, specialist intensive care units,cardiac care units, high dependency units, emergency rooms, operatingrooms, recovery rooms, emergency field situations and/or ambulances.

FIG. 30 illustrates the context for an exemplary system as a standalonecirculatory guidance system. As shown, physiological variables aremonitored using catheters, sensors and transducers attached to thepatient and processed by a standard bedside monitor. Examples of suchbedside monitors are Philips Intelliview, Draeger Infinity, GE Datex, GEMarquette and Spacelabs. An electrical signal cable (or wirelessconnection) may be made to the guidance system which enables it toacquire periodic data from the bedside monitor. The data acquired mayinclude, for example, mean arterial pressure, cardiac output or index,right atrial pressure, heart rate, oxygen saturation. This exemplaryembodiment provides means for user entry of additional patient data(e.g., height, age, weight and hemoglobin), representation of thepatient state and desired state, and guidance on therapy required toachieve the desired state to a clinical user, usually nurse orphysician. The user takes the guidance information along with other datato make a decision about therapy and to initiate or change therapy.Circulatory therapy is usually administered via controlled IV drips,pumps or syringe pumps that are adjusted by the nurse. The care givermay issue orders for therapies. Circulatory therapies may include volume(e.g., saline, blood, and/or colloid), diuretics, vaso-actives and/orcardio-actives.

FIG. 31, illustrates an embodiment where the guidance system isconnected to a bedside monitor and to a specialist cardiac outputmonitor. Examples of such cardiac output monitors may include EdwardsVigileo, Edwards Vigilance, Pulsion PiCCO, Arrow OptiQ and LiDCO. FIG.32 illustrates a configuration of components of a visual display for anexemplary embodiment of a circulatory guidance system includinggraphical, alphanumeric, data entry, status information and text messageitems, or combinations thereof. In certain embodiments, the computerprogram for the circulatory guidance system may run on the computerprocessing elements of a bedside monitor and/or cardiac output monitor.In certain embodiments a circulatory control system could automaticallycontrol the infusion rate of IV pumps and syringes without need for userintervention. Additionally, all, or some, of the visual displaycomponents of FIG. 32 may appear on the visual display unit of the saidmonitor or on another monitor.

For example, FIGS. 33 a-33 d illustrate various exemplary embodimentsfor physically arranging the guidance system with the bedside monitorFIG. 33 a illustrates the guidance system as a free standing computingdevice with power supply, screen, i/o ports, computing hardware etc. Thedevice communicates with standard monitor using serial, USB, Ethernet,wireless, etc using monitor vendor specific protocols and has data entrydevice such as mouse, keyboard, touch screen, thumbwheel or combinationsthereof to introduce external data into fields. FIGS. 33 b 1 and 2illustrate arrangements where the computing device is on a board withpower supply external to but connected to the host monitor and theoutput is transmitted to a window or screen on the host monitor (FIG. 33b 1). In this case, the circulation guidance screen is shared with theconventional monitor screen. Or, as illustrated in FIG. 33 b 2 a freestanding screen may be provided which might be physically separated fromthe computing device. As illustrated in FIG. 33 c, arrangements wherethe guidance software is installed within the standard monitor may alsobe provided or, as illustrated in FIG. 33 d, the guidance software mayexist in a subsidiary monitor. For example, the system of FIG. 33 d maybe provided where the cardiac output is measured with a stand aloneinstrument separate from the standard bedside monitor. The guidancesoftware could then run within the cardiac output monitor. Sucharrangements save on separate power supplies, boards, screens, reducearound bed cables and/or clutter. The instruments may have a symbioticrelationship as the guidance system needs the cardiac output and thecardiac output needs the guidance system for its proper use. The cardiacoutput monitor may support the communications and software to thestandard monitor. In general, the circulation guidance system,particularly the design and operation of the screen is describedthroughout this disclosure and generally embraces control of the various(e.g., 2 or 3) states required to determine the circulatory dynamics.Additionally, volume responsiveness (also described herein) may be usedchose between volume therapy and cardioactive medications.

Certain disclosed systems and/or methods may include, but are notlimited to, representing the subject's actual and desired circulatorystates as a function of mean systemic filling pressure, heart efficiencyand systemic vascular resistance as a visual or audio representation.Visual representations may take the form of bar charts, radial plots,X-Y relational plots or time series charts. In certain embodiments it isdesirable for the representation to have the ability to depict the threequantitative components of mean systemic filling pressure, heartefficiency and systemic vascular resistance. One approach is to use amodified X-Y relational plot in which SVR is on one of the axes andP_(ms) is on the other axis, with the E_(h) scale plotted parallel tothe P_(ms) scale, but moving relative to it. Further exemplaryrepresentations may be 3-dimensional. Additional variables (directlymeasured or derived) pertaining to the circulation may be included onthese graphical, or other, representations for example volumeresponsiveness, blood pressure, heart rate, intrancranial pressure,cardiac output, right atrial pressure, oxygen delivery, etc., orcombinations thereof. These variables may be represented graphically oras textual labels. In some embodiments, no graphical information isdisplayed however guidance on therapeutic intervention is provided innatural language, displayed as text on screen or as audio. In someembodiments, only P_(ms) and SVR are used.

In certain embodiments, the representation of the subjects existingstatus and the target status may be accomplished by use of a variety ofvisual, audio, or combination means. In certain aspects, therepresentation of the subject's circulatory state may often beaccomplished by use of visual, audio or combinations thereof. Certaindisclosed systems and/or methods may include, but not limited to,determining a target direction of a trajectory from the subject's actualcirculatory state to the subject's desired circulatory state on thetwo-dimensional representation, wherein treatment of the subject so asto traverse said trajectory will cause the subject's mean arterialpressure (MAP) and cardiac output (CO) to converge to, and/or movetowards, the subject's desired circulatory state.

Certain systems and/or methods may include, but are not limited to,visually representing the subject's present and desired circulatorystates as a function of certain measured and/or calculated parametersand, if desired, presenting this information in a two-dimensionalrepresentation. Determining a target circulatory state for the subjectbased on certain measured and/or calculated parameters and, if desired,presenting this information in a two-dimensional representation.Providing a direction of a trajectory from the subject's presentcirculatory state to the subject's desired circulatory state and, ifdesired, presenting this information in a two-dimensionalrepresentation. Certain systems and/or methods may include, but are notlimited to, means for visually representing the subject's present anddesired circulatory states as a function of certain measured and/orcalculated parameters and, if desired, presenting this information in atwo-dimensional representation. Means for determining a targetcirculatory state for the subject based on certain measured and/orcalculated parameters and, if desired, presenting this information in atwo-dimensional representation. Means for providing a direction of atrajectory from the subject's present circulatory state to the subject'sdesired circulatory state and, if desired, presenting this informationin a two-dimensional representation. For example, certain disclosedsystems and/or methods may be used to visually represent the patient'scirculatory states as a function of mean systemic filling pressure,heart efficiency, and systemic vascular resistance. The disclosedsystems and/or methods may also be used to determining a targetdirection of a trajectory from the patient's actual circulatory state tothe patient's desired circulatory state and to visually represent thisinformation, wherein the recommended treatment of the patient maytraverse a certain trajectory and may cause the subject's mean arterialpressure (MAP) and cardiac output (CO) to converge to, and/or movetowards, the patient's desired circulatory state. It is to be understoodthat other combinations of measured and/or calculated parameters may beused. For example, cardiac index, oxygen delivery and oxygen deliveryindex, intracranial pressure, intrancranial-arterial pressure differenceand heart rate. Certain disclosed systems and/or methods may include,but are not limited to, visually representing the subject's actual anddesired circulatory states as a function of mean systemic fillingpressure, heart efficiency and systemic vascular resistance as atwo-dimensional representation and determining a target direction of atrajectory from the subject's actual circulatory state to the subject'sdesired circulatory state on the two-dimensional representation, whereintreatment of the subject so as to traverse said trajectory will causethe subject's mean arterial pressure (MAP) and cardiac output (CO) toconverge to, and/or move towards, the subject's desired circulatorystate.

Certain disclosed systems and/or methods may include means forrepresenting the subject's determined and desired circulatory states asa function of systemic filling pressure, heart efficiency, and systemicvascular resistance as a two-dimensional representation. Means forrepresenting the subject's circulatory state may often be accomplishedby use of at least one visual, at least one audio or combinationsthereof. Certain disclosed systems and/or methods may include means fordetermining a target direction of a trajectory from the subject'sdetermined circulatory state to the subject's desired circulatory stateon the two-dimensional representation, wherein treatment of the subjectso as to traverse said trajectory will cause the subject's mean arterialpressure (MAP) and cardiac output (CO) to converge to, and/or movetowards, the subject's desired circulatory state.

Certain disclosed systems and/or methods may include, but are notlimited to, means for visually representing the subject's determined anddesired circulatory states as a function of at least one mean systemicfilling pressure, at least one heart efficiency and at least onesystemic vascular resistance as a two-dimensional representation andmeans for determining a target direction of a trajectory from thesubject's actual circulatory state to the subject's desired circulatorystate on the two-dimensional representation, wherein treatment of thesubject so as to traverse said trajectory will cause the subject's meanarterial pressure (MAP) and cardiac output (CO) to converge to, and/ormove towards, the subject's desired circulatory state.

Certain disclosed methods may include, but are not limited to, visuallyrepresenting the subject's actual and desired circulatory states as afunction of mean systemic filling pressure, heart efficiency andsystemic vascular resistance as a two-dimensional representation anddetermining a target direction of a trajectory from the subject's actualcirculatory state to the subject's desired circulatory state on thetwo-dimensional representation, wherein treatment of the subject so asto traverse said trajectory will cause the subject's mean arterialpressure (MAP) and cardiac output (CO) to converge to the subject'sdesired circulatory state. Certain embodiments relate to therapeuticmaintenance, guidance and/or control of warm blooded animals.

It has been experimentally shown that a determinant of circulatorydynamics may be the mean systemic filling pressure (P_(ms)), defined asthe pressure of an average element in the systemic circulatory network(i.e., between the high arterial pressures and low venous pressure).Historically and in current practice other measures are used tocharacterize the circulatory system which includes left and right heartpressures and volumes and intra-thoracic blood volume. However, thesemeasures are cardio-centric and do not account for the dynamics in thesystemic circulation and the pressures driving venous blood to return tothe heart. P_(ms) can also be defined in certain situations as thepressure that the whole circulation would achieve if the heart stopped.The reason that P_(ms) may be useful in certain embodiments is that itis the pressure driving the return of blood to the right side of theheart, the venous return (VR). According to Starling's Law, the heartwill adjust to pump out blood it receives and hence match cardiac output(CO) to VR. Thus P_(ms) may be a determinant of CO, one of the keymeasures of adequate circulatory function. Surprisingly, the impact ofthis finding on the clinical management of circulatory control has beennegligible because of the lack of a means, and or desire, to measureP_(ms).

However, based on dynamic mathematical modeling of the cardiovascularsystem it can be demonstrated that P_(ms) may be estimated in an“analog” form (P_(msa)) given certain measurements (e.g., measurementsof mean arterial pressure (MAP), right atrial pressure (RAP) and cardiacoutput (CO) and taking into account the age and size of the subject). Incertain embodiments, the estimate may be:

P _(msa) =f(RAP,MAP,CO,c)  (1),

where c is a coefficient dependent on age and size.

More specifically, in certain embodiments, the following linear equationmay be an accurate estimate of the analogue form of the above equation,

P _(msa) =aRAP+bMAP+c(age,size)CO  (2),

where a and b are fixed coefficients for the subjects.

An additional measure of heart effectiveness E_(H) can also beintroduced:

$\begin{matrix}{E_{H} = \frac{P_{ms} - {RAP}}{P_{ms}}} & (3)\end{matrix}$

E_(H) may have the characteristic of being bounded by zero and unity incertain embodiments. When the heart is failing, RAP may rise, therebydecreasing E_(H). When the heart stops, all pressures may besubstantially equal to P_(ms) and hence E_(H) may be substantially equalto zero. In a normally functioning heart RAP is about zero, and henceE_(H) equals about one. In certain embodiments, the analogue form ofequation (1) may be needed to compute equation (2). In certainembodiments, E_(H) may be a measure of how well the heart is performingin the current circulation. In certain equivalent embodiments adifferent mathematical function may be used, using the P_(ms) to rightatrial pressure difference and the current value of P_(ms).

The measurement of P_(ms), or volume state, is useful in many of thedisclosed embodiments because this measurement enables the design anduse of guidance, or closed-loop control, systems for use in criticalcare. Certain embodiments relate to systems, methods and devices formaintenance, guidance and/or control of certain systems for use incritical care wherein P_(ms), is measured or determined as part of theuse of the system, method and device. Certain embodiments relate tosystems, methods and devices for therapeutic maintenance, guidanceand/or control of mammalian circulation using measurement,interpretation, and/or therapy wherein P_(ms), is measured or determinedas part of the use such systems, methods and devices. Certainembodiments relate to computer-assisted methods for therapeutic guidancefor controlling a subject's circulation wherein P_(ms), is measured ordetermined as part of the use of such computer assisted methods.

The measurement of E_(H), or inotropy, is useful in many of thedisclosed embodiments because this measurement enables the design anduse of guidance, or closed-loop control, systems for use in criticalcare. Certain embodiments relate to systems, methods and devices formaintenance, guidance and/or control of certain systems for use incritical care wherein E_(H), is measured or determined as part of theuse of the system, method, and device. Certain embodiments relate tosystems, methods and devices for therapeutic maintenance, guidanceand/or control of mammalian circulation using measurement,interpretation, and/or therapy wherein E_(H), is measured or determinedas part of the use such systems, methods, and devices. Certainembodiments relate to computer-assisted methods for therapeutic guidancefor controlling a subject's circulation wherein E_(H) is measured ordetermined as part of the use of such computer assisted methods.

The measurement or determination of P_(ms) and E_(H) are useful in manyof the disclosed embodiments because these measurements ordeterminations enable the design and use of guidance, or closed-loopcontrol, systems for use in critical care. Certain embodiments relate tosystems, methods and devices for maintenance, guidance and/or control ofcertain systems for use in critical care wherein P_(ms) and E_(H) aremeasured or determined as part of the use of the system, method anddevice. Certain embodiments relate to systems, methods and devices fortherapeutic maintenance, guidance and/or control of mammaliancirculation using measurement, interpretation and/or therapy whereinP_(ms) and E_(H) are measured or determined as part of the use suchsystems, methods, and devices. Certain embodiments relate tocomputer-assisted methods for therapeutic guidance for controlling asubject's circulation wherein P_(ms) and E_(H) are measured ordetermined as part of the use of such computer assisted methods.

The measurements of mean arterial blood pressure (MAP), cardiac output(CO) and right atrial pressure (RAP) reflect the conjoint effects of thedifferent circulatory functions and corresponding therapeuticmodalities. For example, if MAP is low this may be due to a low volumestate or to inadequate heart function. Thus a low MAP could indicate aneed for volume therapy or inotropes (which increase the strength ofcardiac contractions). The space defined by MAP, CO and RAP is one inwhich dimensions confound the effects of therapy.

In certain embodiments, it may improve circulatory control to representthe subject's state in a space where the dimensions are congruent withsingle therapeutic effects. In such a “therapeutic space”, it may bepossible to assess and change therapies with numerical precision, whichmeans arriving at the desired MAP and CO/oxygen delivery faster and moreprecisely (e.g., by selecting the correct modality as well as theamount). Such a space can form the basis for a clinical guidance systemin which the therapy decision is made by the clinician and for schemesof closed-loop or automated control in which the therapy adjustments tointravenous or syringe pumps are made automatically. Such a space canform the basis for a clinical guidance system in which the therapydecision is made by the clinician and for schemes of substantiallyclosed-loop or substantially automated control in which the therapyadjustments to intravenous or syringe pumps are made automatically, orsemi-automatically, (as illustrated in FIG. 34 where the guidance systemcommunicates with the saline pump.

Fluid therapy is one of the commonest therapies in hospital use. Perhaps800 million liters of i.v. fluid are administered annually.Approximately ⅔ of that fluid is 5% dextrose, effectively water, whichis administered to control tonicity or the ion concentration of theplasma. ⅓ of the fluid is N saline or a similar substance includingplasma, the object of which is to control the volume state, i.e.,P_(ms). A smart i.v. fluid system may call on P_(ms) in a guidance orcontrol role and not depend on fluid balance charts which are oftenubiquitous, notoriously inaccurate and time consuming. They mayincorporate tonicity controllers. Since P_(ms) ultimately controls thepower output of the heart (MAP*CO), the target P_(ms) may be determinedby the target power. If P_(ms) is unknown and the patient is volumeresponsive, volume control may be slaved to circulation power. A specialcase for volume controllers exists in patients typically in advancedleft or biventricular failure and/or renal failure. Such patientsfrequently become oedematous and haemofiltration can be used in theircare. Volume guidance/controllers can be used to maintain the finebalance between “too wet” and “too dry”.

Additionally, in some environments there is a requirement to controlMAP. This requires appropriate manipulation of volume, resistance andthe heart. As shown in FIG. 35, the design of the controller includesdevices to control high blood pressure, a common clinical requirement,to elevate MAP in special circumstances (see following) and occasionallyto hold a low blood pressure (e.g., in hypotensive surgery underanaesthesia). An exemplary case of blood pressure control relates topatients with a high intracranial pressure (ICP) where the cerebralperfusion pressure (CPP) (CPP=MAP_ICP) must be maintained. Similarrequirements for MAP elevation exist in patients with vasospasm causingneurological disturbance following subarachnoid haemmorrhage (SAH) orsurgery for SAH. Blood pressure control both up and down may be requiredafter surgery for phaechromocytoma (an adrenal tumour that excretescatecholamines.

Additionally, in certain embodiments an integrated control system maycontrol IV pumps including those for volume, diuretics,vasoconstrictors, vasodilators and/or inotropes in order to provideclosed-loop control for MAP and CO/oxygen delivery.

FIG. 36 illustrates an embodiment of a smart dialysis machines forvolume guidance/control in dialysis. Typically dialysis machines areused in patients in renal failure to take over the function of thekidney. In addition to excreting waste products the kidney (anddialyser) must fulfill the function of controlling the volume state andtonicity in patients who are unable to pass urine. Tonicity control isachieved by dialyzing the patient against dialysis fluids which have anormal tonicity. The patient comes into tonic equilibrium with thedialyser. Volume (P_(ms)) control is normally achieved bydialyzing/filtering off fluid until the appropriate volume state isreached. In haemofiltration extra fluid may be taken off for thefiltrative removal of wastes and replaced with pure saline. In a sickpatient on dialysis maintaining the volume balance may be a demandingprocess. In some embodiments, P_(ms) based volume controllers may beincorporated into dialysis machines so that the volume state may beguided or servo controlled. This is probably the first environment intowhich volume servo control will be introduced, the availability ofdialysis to avoid the possibility of hazardous overshoots making itparticularly safe. Equally the availability of circulation guidance andvolume servo control may be a very useful adjunct to the management ofthe circulation in critically ill patients in renal failure, forexample, patients in septic shock. Modern dialysis machines seek tomaintain circulatory volume balance where volume in equals volume outstrategy. This takes no account of the internal distribution of fluidsand how much is lost to or gained from the interstitial or “third space”compartments. It is time for a more sophisticated approach. Rather thanregulating the loss/gain of the dialyser by shifting the position of thezero transmembrane pressure point one can set the dialyser to lose fluidand then servo control volume replacement with a simple P_(ms)controlled on/off clamp on a volume replacement line.

Further, the guidance system information may be useful for regulation ofthe circulation in patients in whom there is a heart/lung machine,ventricular assist device, artificial heart, etc. Unlike the normalheart, the output of which is servo controlled to the input, mechanicalhearts are not thus regulated. A problem with ventricular assist devicesfor example has been “stalling” when the pump output is not matched bythe venous return. Since P_(ms) regulates the venous return, P_(ms)based controllers may provide more understanding in the care of patientswith mechanical hearts.

A canonical representation (e.g., one that reduces to simpler andsignificant form without loss of generality) is generally not possiblewithout using the mean systemic filling pressure and heart efficiencyderived variables as in equations (1) and (2). In certain embodiments,the dimensions of this new space may include:

1. analogue mean systemic filling pressure (P_(msa)), which relates tovolume increasing or volume decreasing therapy;

2. heart efficiency (E_(H)), which relates to cardioactive therapiesincluding inotropes, chronotropes and lusitropes; and

3. systemic vascular resistance (SVR), which relates to vasoconstrictorand vasodilator therapy and may be defined as:

$\begin{matrix}{{SVR} = {\frac{80\left( {{MAP} - {RAP}} \right)}{CO}\mspace{14mu} {{dynes}.{cm}^{- 5}.\sec}}} & (4)\end{matrix}$

A position in the {P_(ms), E_(H), SVR} space can be determined fromequations (1) to (4) for both the patient's actual state {P_(ms), E_(H),SVR}_(act) and a desired patient state {P_(ms), E_(H), SVR}_(des). It iscustomary to prescribe the desired patient state in terms of MAP and CO(or oxygen delivery), but not RAP. By comparing the elements of {P_(ms),E_(H), SVR}_(act) and {P_(ms), E_(H), SVR}_(des), it is possible toassess the overall change required in each element (therapy modality) toachieve the desired therapy.

In certain embodiments, the 3-dimensional {P_(ms), E_(H), SVR} space maybe depicted in two dimensions without loss of, or substantial loss of,information. For example, as shown in FIG. 1, this may be achieved byplotting SVR as the abscissa (x-axis) and P_(msa) as the primaryordinate (y-axis). Equation (2) may then used with the current RAP valueto determine a second scale on the ordinate for E_(H), as shown inFIG. 1. As RAP changes, the relationship between the P_(msa) and E_(H)scales changes (i.e., the scales move relative to each other). It shouldbe noted that if P_(msa) is a linear scale, then E_(H) may be anon-linear scale. The symbol P_(ms) in certain embodiments may be usedfor the analogue form P_(msa). In certain embodiments, the 3 coordinates{P_(ms), E_(H), SVR} space may be depicted in other 2 dimensionalrepresentations such as bar charts, polar or radial charts, multipletime series charts and in 3 dimensional representations. In certainembodiments, other numeric variables may be added to provide additionallabeling or dimensions.

The current patient state 110 is indicated on the graph of FIG. 1. Incertain embodiments, a useful way to draw FIG. 1 may be to position thecenter of the chart, where the axes cross, at the desired circulation orpatient state 120. It is then apparent to the observer in what directionand by how much the 3 variables need to change in order to acquire thedesired circulation. These three variables are volume state, systemicvascular resistance and heart efficiency. Without the system it isfrequently hard to determine the needed changes and they do not alwaysmatch clinical intuition. For example, without the system a low bloodpressure and cardiac output may suggest need for volume therapy. Withthe system, it may become apparent whether cardiac inotropes arerequired instead, and whether vaso-active therapy is needed. A fall inE_(H) to very low values (for example, an E_(H)<0.3 in humans) mayindicate not only that the heart is failing, but that there may be otherphysical impediments impeding venous return or sufficient cardiacfunction. These may include abnormally high intra-thoracic pressure andcardiac tamponade. In clinical practice, differential diagnosis may beindicated for low E_(H). Once physical impediments have been ruled out,a low E_(H) can indicate the need for cardiac medications, including,but not limited to, inotropes, chronotropes, lusitropes or combinationsthereof.

Having determined the distance from the actual position 110 to thedesired position 120 on the 3 axes in the therapeutic space, it remainsto determine the path of therapeutic maneuvers to achieve the desiredcirculation. For example, if a subject requires volume andvasodilatation which should be given first? Does the order of therapymatter? This can be described as the tactical problem—what to donow—whereas the overall change is the strategic problem. The tacticalproblem is non-trivial and it does not generally follow that alltherapies should be given simultaneously and in direct line to thetarget. In fact, it may be dangerous to proceed in that direction. Forexample, a patient may need filling and vasodilatation. However, if theyare dilated first with a low blood pressure, there is a risk of furtherdrop in blood pressure and consequent shock and organ failure. In thiscase it is important to fill prior to dilating. The various embodimentsdisclosed provide methods for selecting the appropriate, orsubstantially appropriate, treatment sequencing decisions and avoiding,or substantially avoiding, the inappropriate ones. It is the avoidance,or substantial avoidance, of inappropriate treatment choices (and/orsequences) that enables the disclosed system(s) to provide better, orimproved, circulatory care and reduced risk of side effects. Thesystem(s) disclosed provide various means to determine the appropriatesequence and/or order of therapy. In practice, the subject's state maybe continually changing and both strategic situational assessment andtactical treatment change may need constant re-consideration. Thesefacts, coupled with the complex underlying circulatory dynamics, makethis a challenging and non-trivial issue. The system provides a means tocontinuously assess the patient's state and select appropriate short andlong term therapy in order to adjust to the changing patient conditionand to the effects of treatment. It enables improved circulatory controland the avoidance of situations in which side effects can occur.

In certain embodiments, a method for solving this problem is to considerthat the subject's current observed state is {MAP, CO}_(act) and thedesired state is {MAP, CO}_(des). The aim of tactical therapy choice isto drive both MAP and CO monotonically closer to the desired state andto not move further away. Two steps are often required to determine anoptimal trajectory to the desired state. First, project lines ofconstant MAP and CO/oxygen delivery on the {P_(ms), SVR} space (it isnot necessary to consider E_(H) as it is a function of P_(ms)). Theselines are referred to as the MAP and CO isograms. Second, determine theoptimal trajectory relative to the isograms to achieve the aim oftactical therapy. This method can be applied regardless of whichgraphical method of representation has been selected. The 2 dimensionalX-Y relational plot depicted in FIG. 1 is a practical and usablerepresentation for these purposes, but not the only one.

The isograms are derived from equations (1), (2) and (4) and expressP_(ms) as a function of SVR. These may be obtained from equation (1)using the SVR equation (3) to substitute for MAP or CO, respectively.The linear form of equation (2) may also be used.

The MAP isogram may be defined by:

P _(ms) =f _(MAP)(SVR, MAP,RAP_(Act) ,c)  (5)

Where, MAP denotes constant MAP for a given isogram; and

RAP_(Act) is the actual current measured value of RAP.

The linear form obtained by substituting into equation (2) may be:

$\begin{matrix}{P_{ms} = {{aRAP}_{Act} + {b\overset{\_}{MAP}} + \frac{80\mspace{14mu} {c\left( {\overset{\_}{MAP} - {RAP}_{Act}} \right)}}{SVR}}} & (6)\end{matrix}$

The CO isogram may be defined by:

P _(ms) =f _(CO)(SVR, CO,RAP_(Act) ,c)  (7)

where CO denotes constant CO for a given isogram.

The linear form may be:

$\begin{matrix}{P_{ms} = {{RAP}_{Act} + {c\overset{\_}{CO}} + \frac{b{\overset{\_}{CO}.{SVR}}}{80}}} & (8)\end{matrix}$

FIG. 2 shows MAP and CO isograms projected on the {P_(ms), SVR} space ofFIG. 1 in accordance with certain embodiments disclosed herein. Isograms210 and 220 are MAP isograms for the actual (Act) and desired (Des)patient states, respectively, and isograms 230 and 240 are CO isogramsfor the actual (Act) and desired (Des) patient states, respectively.

Usually a trajectory contained within the inner angle between the MAPand CO isograms will take both variables closer towards their targetvalues. As shown in FIG. 2, the inner angle 250 is the angle in thequadrant containing the desired target state. An effective exemplarysolution, which provides a locally optimal therapeutic guidancetrajectory, is to bisect the inner angle. If a variable is close to oron its target, then the optimal guidance trajectory typically willfollow along the isogram relating to that variable in the directionwhich takes the other variable closer to its target. This may beaccomplished by using weighting functions in combining the angles thattake into account the proportional distance from the desired targetvalues of each of the variables. Specifically, in an exemplaryembodiment, a computer-assisted method/computer program/system fordetermining the optimal treatment for volume, resistance and heart basedon projecting lines of constant MAP and CO onto a geometric space withthe coordinates of P_(ms) and SVR, with the angles formed between theintersecting MAP and CO lines and consideration of the location of thetarget indicating the optimal treatment may be used. The value of E_(h)may be used to assist in determining whether volume or heart therapy isrequired or both. A correction is made to allow for the closeness of MAPand CO to their target values. In general the basis of this algorithm isabstract geometry and the mapping between a {MAP,CO} space and a {Pms,Eh} space.

An embodiment for determining the optimal trajectory is described withreference to FIG. 3. Referring to FIG. 3, a subject's actual circulatorystate 310 and desired circulatory state 320 are shown as points on the{P_(ms), SVR} space. Actual CO and MAP isograms 312 and 314,respectively, intersect at the subject's actual circulatory state 310.φ_(CO) is the acute angle formed between the CO isogram 312 and thehorizontal 330. φ_(MAP) is the obtuse angle formed between the MAPisogram 314 (or a tangent 316 to the MAP isogram 314 at the subject'sactual circulatory state 310) and the horizontal 330. The optimalguidance trajectory 340 may be specified by a vector at an angle θ tothe horizontal 330. Algorithmic steps for determining the optimaltrajectory may be as follows:

1. Compute φ_(CO)

2. Compute φ_(MAP)

3. Compute weighting functions ω_(CO) and ω_(MAP)

4. Adjust φ_(CO) and φ_(MAP) for inner angle (depending on positionrelative to target)

5. Compute the optimal guidance trajectory using:

$\begin{matrix}{\theta = \frac{{\omega_{MAP}\varphi_{CO}} + {\omega_{CO}\varphi_{MAP}}}{\omega_{MAP} + \omega_{CO}}} & (9)\end{matrix}$

In certain embodiments, this approach may be beneficial since thepatient state may evolve moment-to-moment and the guidance trajectorymay change.

A specific realization of the foregoing algorithmic steps usingequations (6) and (8) for the isograms, the method of bisection of theinner angle, and a hyperbolic tangent as weighting function is:

$\begin{matrix}{\varphi_{CO} = {\tan^{- 1}({bCO})}} & (10) \\{\varphi_{MAP} = {{2\pi} - {\tan^{- 1}\left\lbrack \frac{c\left( {{MAP}_{Act} - {RAP}_{Act}} \right)}{\left( \frac{SVR}{80} \right)^{2}} \right\rbrack}}} & (11) \\{\omega_{CO} = {\tanh \left\lbrack {\beta {\left( \frac{{CO}_{Act} - {CO}_{Des}}{{CO}_{Des}} \right)}} \right\rbrack}} & (12) \\{\omega_{MAP} = {\tanh \left\lbrack {\beta {\left( \frac{{MAP}_{Act} - {MAP}_{Des}}{{MAP}_{Des}} \right)}} \right\rbrack}} & (13)\end{matrix}$

Typically; β=20

Adjustments for the inner angle:

MAP_(Act)>MAP_(Des)

φ_(CO)←φ_(CO)+π  (14)

CO_(Act)<CO_(Des)

φ_(MAP)←(φ_(MAP)+π)mod 2π  (15)

CO_(Act)>CO_(Des)∩MAP_(Act)<MAP_(Des)

φ_(MAP)←φ_(MAP)−2π  (16)

The optimal tactical guidance trajectory may be given by:

$\begin{matrix}{\theta = \frac{{\omega_{MAP}\varphi_{CO}} + {\omega_{CO}\varphi_{MAP}}}{\omega_{MAP} + \omega_{CO}}} & (17)\end{matrix}$

As a vector in the {P_(ms), E_(H), SVR} space, θ resolves into therequired therapeutic changes in each of these dimensions. The θ vectorcan be depicted as a “compass” arrow on the {P_(ms), E_(H), SVR} chartfor guidance, determine the direction of therapy on bar charts, othervisual representations, or can be used as the input into a closed loopautomated controller for administering relevant therapies.

In certain embodiments, a decision table may be combined withcomputer-assisted methods to provide therapeutic guidance. In certainembodiments, a decision table may be used to select therapeutic guidanceor direction.

An example is shown below. A guidance to use inotropes to increase heartstrength can be made by examining the value of E_(h), eg E_(h)<0.3. Ifthis is not available, the guidance may be computed using SVV or PPVmeasures from certain cardiac output monitors.

SVR Condition Volume/Heart Guidance Guidance MAP < MAPdes CO < COdesIncrease Heart/Volume Hold MAP >= MAPdes CO < COdes Hold Heart/VolumeDecrease MAP < MAPdes CO >= COdes Hold Heart/Volume Increase MAP >=MAPdes CO >= COdes Decrease Volume Hold

In certain embodiments of the visual representation, including but notlimited to, a 2D bar chart display, recommended changes in treatment canbe shown as changes to target. For example, if the current guidance isto hold the volume state, then the target volume state value can be setto the current volume state value. A similar approach can be used forother controlled variables. This can be referred to as a “dynamictargets”.

FIG. 4 shows a system for circulatory monitoring and guidance inaccordance with certain embodiments. The circulatory monitoring andguidance system 410 may be employed to assist clinical users intargeting, assessing and managing the circulatory system of patients incritical care. A benefit of the circulatory monitoring and guidancesystem 410 may include improved control of the circulatory state andreduction of side effects associated with poor control of thecirculatory state.

The circulatory monitoring and guidance system 410 is shown coupled to abedside monitor 420 and a cardiac output monitor 430. The bedsidemonitor 420 and cardiac output monitor 430 are coupled to a patient 440.A clinician or medical practitioner 450 may use the circulatorymonitoring and guidance system 410 to monitor and control circulation ofthe patient 440. The circulatory monitoring and guidance system 410 maybe coupled to the bedside monitor 420 and cardiac output monitor 430 viaa wired or wireless interface.

The circulatory monitoring and guidance system 410 comprises a number ofsoftware modules including a data acquisition module 412, a datapre-processing module 414, a computation module 416 and a graphicaldisplay and user interaction module 418. The data acquisition module 412communicates with the bedside monitor 420 in accordance with a definedcommunications protocols to request and receive data at defined rates.An example of a practical sampling rate is about once every 5 seconds.In some embodiments a 2-5 sec, 3 sec or 4 sec, rate may appropriate whenthe patient's cardiac output is being monitored continuously with pulsecontour methods (for example on Vigileo, PiCCO or LidCO devices). Thisenables the user to see the immediate effect of therapy and short-termchanges in the patient. When cardiac output is measured with continuouspulmonary catheter methods (e.g., Vigilance, OptiQ), sampling rates of 5sec-5 min (e.g., 5 sec, 10 sec, 30 sec, 45 sec, 1 min, 2 min, 3 min, 4min or 5 min) are appropriate. When cardiac output is measuredintermittently (e.g., with thermodilution or ultrasound) it may beappropriate to sample cardiac output at longer times (e.g., from 5 minto 2 hours, 20 min, 1 hour, 1.5 hours, etc.). In this latter case,however, cardiac output between samples may be interpolated using pulsecontour information from the arterial pulse or the oxygen saturationpulse, which enables the guidance or control system to be usedcontinuously (a 2-5 sec time sensitivity). MAP and RAP measurements aretypically available from standard bed side monitors. Cardiac output COmay be available from certain bed side monitors but may otherwise and/orobtained from a dedicated CO apparatus. The data pre-processing module414 receives data from the data acquisition module 412 and performsrange checking, artifact rejection and filtering to reduce unwantednoise signals. Suitable filters eliminate changes with, for example,sub-1 minute dynamics. Input data may be invalid for various reasonsincluding temporary use of a catheter line for other purposes, blockage,patient lying on top of line, transducers being incorrectly leveled andso forth. When data is received, values may be inspected by algorithmsto detect these events and to exclude these data points. One method todo this is to exclude values which fall out of pre-defined ranges suchas 0-200 mmHg for MAP, −1-30 mmHg and less than 40% oxygen saturationand 0-20 L/min for cardiac output. Filtering following artifactrejection may be performed to reduce short-term variation or noise inthe data streams. A moving average or median filter with a 95% responsetime of 1 min is satisfactory for blood pressure signals and continuouscardiac output signals. When cardiac output is obtained intermittently,there may be no need to filter it. Right atrial pressure signalsfrequently have only single digit precision. Filtering of the signalsmay be beneficial to provide interpolated values and smoother changes toavoid “jump” effects. There may be other methods for artifact rejectionwhich may be used, for example, a median or other non-linear filter witha time window (e.g., 1 min, 5 min and 10 min) applied iteratively to theincoming data streams. The computation module 416 receives processeddata from the data pre-processing module 414 and performs a series ofcomputations. The graphical display and user interaction module 418enables a user to enter patient anthropometric data, and to view thenumerical values of key variables. The graphical display and userinteraction module 418 displays numerical and graphical representationsof the patient's circulation.

The modules described hereinbefore with reference to FIG. 4 may comprisecomputer software modules and may reside on an embedded computer systemor a general purpose computer system such as the computer system 800described hereinafter with reference to FIG. 8. In an alternativeembodiment, the Circulatory Monitoring and Guidance System 410 may beintegrated into a bedside monitor and/or cardiac output monitor. In yetanother alternative embodiment, the data acquisition module 412 may beintegrated into a bedside apparatus such as the bedside monitor 420 orthe cardiac output monitor 430. This embodiment enables the datapre-processing module 414, the computation module 416 and/or thegraphical display & user interaction module 418 to be hosted and/orexecuted by a computer system, such as the computer system 800 describedhereinafter with reference to FIG. 8, located remotely from thepatient's bedside. It will appreciate that certain of the modulesdescribed with reference to FIG. 4 may cooperate with additionalelectronic circuitry or hardware. For example, the data acquisitionmodule 412 typically cooperates with an electronic circuit for samplingand processing data under software control (e.g., an analogue-to-digitalconverter).

FIG. 5 is a flow chart of a method implementable as a computer softwareprogram for controlling a computer system such as the CirculatoryMonitoring and Guidance System 410 of FIG. 4 in accordance with certainembodiments. In step 510, a user enters patient anthropometric and otherdata, including age (A, years), height (H, cm), weight (W, kg), andhaemoglobin (Hb). In step 520, computations are performed to determinethe patient's body surface area (BSA, m²), a typical cardiac index forthe patient's age (CI_((A)), L/min/m²), and the corresponding cardiacoutput (CO_((A)) L/min). These values may be determined using equations(18)-(20), hereinafter:

BSA=0.007184H ^(0.725) W ^(0.425)  (18)

CI_((A))=4.5(0.99)^((A-15)*)  (19)

CO_((A))=CI_((A))BSA  (20)

The age-adjusted norm mean arterial pressure (MAP_((A))) is:

MAP_((A))=94.17+0.193A  (21)

The coefficients a, b, c in equation 22 hereinafter are given by:

a = 0.96 b = 0.04 $c = {0.038\frac{{MAP}_{(A)}}{{CO}_{(A)}}}$

In step 530, the user sets desired target values for mean arterialpressure (MAP) and cardiac output (CO). It is useful in practice to beable to enter these values as upper and lower values, which define a“target zone”. In step 540, actual patient data is obtained from devicessuch as bedside monitors and may be pre-processed as describedhereinbefore. The raw data may be displayed in numeric format on thedisplay screen. A status indicator may show whether data have beenreceived on time, whether there are disconnections, range errors and soforth. In step 550, various derived variables are computed for theactual (“Act”) patient state:

Mean systemic filling pressure:

P _(msAct) =aRAP_(Act) +bMAP_(Act) +cCO_(Act)  (22)

Systemic vascular resistance:

$\begin{matrix}{{SVR}_{Act} = {80\left( \frac{{MAP}_{Act} - {RAP}_{Act}}{{CO}_{Act}} \right)}} & (23)\end{matrix}$

In step 560, a graphical representation showing the direction of theoptimal therapeutic trajectory is displayed on a display screen. Thepatient's position is determined by equations (27) and (28). Thedirection of the optimal therapeutic trajectory is determined usingequations (10) to (17). In step 570, a determination is made whether theuser wishes to quit. If not (N), the method reverts to step 540 foracquisition of new patient data. If the user does wish to quit (Y), themethod is terminated at step 580.

FIG. 6 shows an example of a graphical representation that may bepracticed to perform step 560 of the method of FIG. 5 in accordance withcertain embodiments. One convenient arrangement may be to position themean target or desired patient state 610 at the centre of the graphicalrepresentation. A zone 620 representing the target range of MAP and COfor the patient may be displayed by computing and graphing the isogramscorresponding to the upper and lower target values of both variablesusing equations (6) and (8), hereinbefore. The patient's actual positionis shown as a “compass” arrow 630, which points in the direction of theoptimal therapeutic trajectory. The direction of the optimal therapeutictrajectory is generally not directly towards the desired patient state610. In practice, the graphical representation may be re-drawn with eachnew set of patient data. Both the axes and patient position move. Aneffective way is for the axes to slide on the display, giving theimpression of a virtual instrument. The E_(H) scale is plotted alongsidethe P_(ms) scale consistent with equation (3) using the current actualvalue of RAP. Over time, this creates the effect of the two scalesmoving relative to each other. Values of E_(H) below a threshold (e.g.,0.3) may be indicated by differently colored scale labels. If thepatient's E_(H) is low an advisory message may be generated explainingpotential causes and suggesting appropriate investigations andtreatment.

Certain embodiments methods and/or systems for critiquing currenttherapy and, if different to that advised by the circulatory monitoringand guidance system, to advise a user of this fact and of appropriatecorrective action. FIG. 7 shows a block diagram of a system forcritiquing current therapy that is similar to the circulatory monitoringand guidance system 410 of FIG. 4 in accordance with certainembodiments. Referring specifically to FIG. 7, the current intravenousinfusion rates of volume, cardiac and vasoactive medications areacquired from the IV and/or syringe pumps 760 via the Data AcquisitionModule 412. The current rates are compared with the guidance from thecirculatory guidance system as described hereinbefore with reference toFIGS. 4 to 6, by the therapy critiquer module 717. If there is avariance, an explanatory warning message may be provided to a user viathe display screen. Alarms or text messages may also or alternatively begenerated. Certain embodiments illustrated herein (see FIG. 7) enablesautomatic control of circulation to be implemented by controlling theinfusion rates of particular medications.

FIG. 8 shows a schematic block diagram of a computer system 800 that canbe used to practice the methods described herein. For example, thecomputer system 800 may be used to implement the Circulatory Monitoringand Guidance System 410 of FIG. 4. More specifically, the computersystem 800 provides a hardware platform that may be used to executecomputer software such as the computer software module describedhereinbefore with reference to FIGS. 4 and 7. Accordingly, the computersystem 800 may be programmed to assist in performing a method thatprovides therapeutic guidance for controlling a subject's circulation.The computer software executes under an operating system such as MSWindows XP™, MS Windows VISTA™ or Linux™ installed on the computersystem 800.

The computer software involves a set of programmed logic instructionsthat may be executed by the computer system 800 for instructing thecomputer system 800 to perform predetermined functions specified bythose instructions. The computer software may be expressed or recordedin any language, code or notation that comprises a set of instructionsintended to cause a compatible information processing system to performparticular functions, either directly or after conversion to anotherlanguage, code or notation.

The computer software program comprises statements in a computerlanguage. The computer program may be processed using a compiler into abinary format suitable for execution by the operating system. Thecomputer program is programmed in a manner that involves varioussoftware components, or code, that perform particular steps of themethods described hereinbefore. The components of the computer system800 comprise: a computer 820, input devices 810, 815 and a video display890. The computer 820 comprises: a processing unit 840, a memory unit850, an input/output (I/O) interface 860, a communications interface865, a video interface 845 and a storage device 855. The computer 820may comprise more than one of any of the foregoing units, interfaces,and devices. The processing unit 840 may comprise one or more processorsthat execute the operating system and the computer software executingunder the operating system. The e memory unit 850 may comprise randomaccess memory (RAM), read-only memory (ROM), flash memory and/or anyother type of memory known in the art for use under direction of theprocessing unit 840. The video interface 845 is connected to the videodisplay 890 and provides video signals for display on the video display890. User input to operate the computer 820 is provided via the inputdevices 810 and 815, comprising a keyboard and a mouse, respectively.The storage device 855 may comprise a magnetic or optical disk drive, orany other suitable non-volatile storage medium.

Each of the components of the computer 820 is connected to a bus 830that comprises data, address and control buses to allow the componentsto communicate with each other via the bus 830.

The computer system 800 may be connected to one or more other similarcomputers via the communications interface 865 using a communicationchannel 885 to a network 880, represented as the Internet.

It will appreciate that the computer system 800 may be connected orinterfaced to other external devices via the communications interface865 or the input/output (I/O) interface 860. For example, the bedsideand cardiac output monitors 420 and 430 shown in FIGS. 4 and 7 may beinterfaced to the computer system 800 via the communications interface865 (e.g., RS-232, RS-485 or Universal Serial Bus (USB)). The IV pumps760 shown in FIG. 7 may be interfaced to the computer system 800 via theinput/output (I/O) interface 860 using an analogue-to-digital converter.

The computer software program may be provided as a computer programproduct and recorded on a portable storage medium. In this case, thecomputer software program is accessible by the computer system 800 fromthe storage device 855. Alternatively, the computer software may beaccessible directly from the network 880 by the computer 820. In eithercase, a user can interact with the computer system 800 using thekeyboard 810 and mouse 815 to operate the programmed computer softwareexecuting on the computer 820.

The computer system 800 has been described for illustrative purposes.Accordingly, the foregoing description relates to an example of aparticular type of computer system such as a personal computer (PC),which is suitable for practicing the methods and computer programproducts described herein. However, it will be appreciated thatalternative configurations or types of computer systems may be used topractice the methods and computer program products described herein. Forexample, but not limited to, an embedded computer system may be used inplace of the general purpose computer system 800. In such a system, thevideo display 890 and keyboard 810 of the computer system 800 may beintegrated into the housing of the embedded computer system.

In certain embodiments, the circulatory monitoring and guidance systemmay be provided on a medically rated bedside touch-panel computer (e.g.,Advantech POC153M or POC-S155). It may be connected to bedsidephysiological monitors in critical care environments. The connectionfrom the circulatory monitoring and guidance system to the bedsidephysiological monitor may be via, for example, a serial cable connectedto the COM 1 (RS232) or COM2 (RS422) port on the back of the computer.Cardiac output data may be obtained directly from the circulatorymonitoring and guidance system or from a separate cardiac output monitorconnected by serial cable to the COM 3 port. In certain embodiments, thecirculatory monitoring and guidance system may automatically acquiredata from the monitor(s) every five (5) seconds. Variables acquired mayinclude mean arterial pressure (MAP mmHg), right arterial pressure (RAPmmHg), cardiac output (CO L/min) and arterial oxygen saturation (SaO₂%).In certain embodiments, the data may be filtered, smoothed and artifactsrejected.

The circulatory monitoring and guidance system may help clinicians settargets for the desired circulation, assess, in real time over theperiod of a few heartbeats, the current state of the patient's systemiccirculatory state in relation to the target, and decide on appropriatetreatment with reference to volume, cardioactive (inotropes andlusiotropes) and vasoactive (vasodilator and vasoconstrictor) therapies.Circulatory and heart changes take place more slowly than a few heartbeats (e.g., minutes to hours) but given the severity of illness of somepatients it is helpful to be able to see their circulatory stateevolving with this level of time detail. Following administration ofcardiac agents such as inotropes it is clinically beneficial to see howthe patient is responding on this fast timescale. The guidance orcontrol system provides great benefit when used with cardiac outputmethods responsive on this time interval such as PiCCO, LidCO orVigileo.

As discussed herein, and with respect to FIG. 9, in certain embodiments,the main display of the circulatory monitoring and guidance system mayshow a graphical depiction of the patient's state in relation to adesired target. The mean systemic filling pressure (right hand sidevertical scale) (P_(ms)) is a measure of volume state, or how wellfilled the circulation and is a prime determinant of venous return andcardiac output. The heart efficiency (E_(H)≧0) (left hand side of thescale) is a measure of global heart performance. It is sometimesreferred to as the heart performance.

In certain embodiments, the clinician sets a target mean value for MAPand CO. The CO target mean may also be set through the correspondingcardiac index (CI). The center of the graph (where the axes cross)corresponds to the mean target MAP and CO. The “diamond” shape aroundthe centre indicates the upper and lower limits of the desired targetstate.

When mean values are set for the targets, the default ranges may be setto, for example, about ±5-15% (e.g., ±5, ±7, ±9, ±10, ±11, ±13, ±14,etc.) for MAP and about ±7.5-15% (e.g., ±8, ±9, ±10, ±11, ±13, ±14,etc.) for CO and CI.

The user can identify where the patient (the solid dot in the arrow) isin relation to the desired circulation and assess the kind ofintervention needed to take the patient to the target. A directionalarrow on the patient symbol shows the next order of therapy. Thedirection is that which will take both MAP and CO closer to their targetvalues.

The circulatory monitoring and guidance system may be applicable tocritically ill patients requiring circulatory support in which MAP, RAPand CO are being monitored regularly. This includes a broad range ofpatients with unstable circulations presenting to the ICU critical careunits, with exemplary conditions including, for example, patients aged18 years or older, pre & post open heart surgery, pre & post majorsurgery, septic shock, renal failure, major burns, major trauma andcardiogenic shock.

In some embodiments, the circulatory monitoring and guidance system mayrequire some data that is entered manually and other data that isacquired automatically from bedside devices. For example, in certainembodiments, the following anthropometric and other data items may beentered manually using the touch screen: patient initials, age (years),height (cm), weight (kg) and haemoglobin (g/L).

Additionally, in order to function, the circulatory monitoring andguidance system may use the following variables: MAP (via directarterial measurement or non-invasive blood pressure), cardiac output(CO) and right atrial pressure (RAP & CVP are used interchangeably).

If arterial oxygen saturation (SaO₂) is available, certain embodimentswill use this value to calculate and display oxygen delivery indexvalues (DO₂I) corresponding to the lower and upper CO range. It isimportant to note the accuracy of the DO₂I values may depend on having arecent value of the haemoglobin.

In an exemplary embodiment, the circulatory monitoring and guidancesystem may launch in the manner illustrated in FIGS. 10-18.

After powering on as shown in FIG. 10, the circulatory monitoring andguidance system may wait to receive data from the bedside monitor. Thedata link status indicator in the bottom right hand corner is set to themessage “Awaiting Data”. Once the data from the bedside and cardiacoutput monitors appears on the screen (FIG. 11), the data link statusindicator typically now show the message “Data Link OK” and the userwill typically confirm correlation of the values on the circulatorymonitoring and guidance system with bedside monitor values. To set upthe device for a new patient, the user may use a touch-sensitive screenon the device and touch the “New Patient” button in the menu area tostart setting up a new patient (see FIG. 12).

Using the Alpha numeric keypad shown in FIG. 16, the user may enter inthe following information:

1. Patient Initials: First Initial First name, first initial last name.

2. Age (years)

3. Height (cm)

4. Weight (kg)

5. Haemoglobin (Hb, g/L)

In certain embodiments, the patient's height and weight may be used tocalculate body surface area (BSA), which is subsequently used incalculating cardiac index (CI) therefore it may be important that thesevalues are accurate. Once complete, the screen in FIG. 17 appears andmean target values for MAP and CO can be set by touching the fielddisplaying the mean desired value, to the right of the two fieldsdisplaying the higher and lower values of the target range and enteringthe desired mean target using a pop-up keypad, for example. The initialvalue used is that specified at the patient randomization stage. Thedevice will automatically set the higher and lower target ranges to, forexample, ±12% of the mean for MAP and ±12% for CO or CL (The defaultvalues of 75 mm hg for a CO of 5 liters/rain may also have been set.)

As shown in FIG. 17, CI (Norm) is the normal resting age determined CI,the value of which has been determined by using a normalized CI v AgeCurve. The age dependant normal cardiac index is provided as a guide fortargeting cardiac output or cardiac index with the device. The CI (Norm)may not be suitable as a target cardiac index for all patients. The CIis determined at normal body temperature (37° C.) and in the hypo- orhyperthermic patient a good rule of thumb is to reduce (hypothermia) orraise (hyperthermia) the normalized CI by 7-10% per degree C. to allowfor the temperature effect.

Although the normalized resting cardiac index is a starting point,consideration may then be given to the following conditions:

1. Adequate and appropriate oxygen transport variables: these areconventional and include D0₂, D0₂I, V02, mixed venous pv0₂, Sv0₂, pH,lactate, etc.

2. Hydraulic variables. Some patients will require for example a highercardiac output for purely hydraulic reasons, e.g., Fistula, recentreplacement of a stenotic valve, diseases with low SYR. Setting ofnormal cardiac output/index targets would require undesirablevasoconstriction to maintain MAP targets.

3. The State of the patient's heart. Consideration of what themyocardium is capable of is an issue in the determination of cardiacoutput control targets. This relates to both upper and lower bounds. Thevalue of E_(H) is helpful in this regard.

4. Power Reduction. If the above three conditions are accounted for,consideration may be given to lowering cardiac output targets and reduceheart work.

As shown in FIG. 18, on the vertical axis (to the right) is the meansystemic filling pressure (P_(ms)) scale, which is the measure offilling of the circulation (volume state). It is a prime determinant ofvenous return and cardiac output. Also displayed on the vertical axis(to the left) is the heart efficiency scale E_(H)—this is a measure ofglobal the heart performance (efficiency). The P_(ms) and E_(H) scalesare independent. On the horizontal axis is the systemic vascularresistance scale, SVR.

Referring to FIG. 18, the numeric panel on the right hand side of thedisplay shows the data acquired from the monitors, the patient's currentstate is shown as a solid circle, in a arrow or “compass”. The arrowindicates the next therapeutic direction. The direction of this arrowcorresponds to one which takes the MAP and CO closer to their targets(based on the relationships that P_(ms), E_(H) and SVR have with MAP andCO). The scale on the y-axis where heart efficiency (E_(H)) is less than0.3 appears with red labels. The use of inotropes may be indicated inthis area.

A would be readily understood in view of the present disclosure,widespread realization of good circulation control at the bedsiderequires intelligent targeting and consistent continuous guidance.Adoption of such an approach relieves the clinician of the repetitiveburden of the (sometimes inconsistent) task of therapeutic design.Certain embodiments disclosed herein are directed to standardization andconsistency. For example, the direction of the patient “compass” symbolshows the direction of the therapeutic change that will move the patientmonotonically to the target. The immediate direction may not always betowards the center. Additionally, the desired circulation will betypically continuously achieved if the patient symbol is maintained inthe appropriate quadrilateral.

The vertical scale on the right through the centre shows the volumestate (Pms) in mmHg and administering volume will move the patientsymbol upwards; diuretics/diuresis, dialysis and venodilators will movethe patient symbol downwards. The horizontal scale shows the arterialresistance (SVR) in SI units (×100). Arteriolar vasodilators (e.g. GTN,SNP) will move the patient to the left; vasoconstrictors (e.g.noradrenalin, metaraminol and/or vasopressin) will move the patient tothe right.

In certain embodiments, approximately 70-80% of circulation control willbe safely achieved with +/−volume and +/−arterial vasoactives. A secondand independent vertical scale indicates the state of performance of theheart. The heart performance E_(H) is given by E_(H)=(Pms−RAP/P_(ms)).The heart performance works together with the volume state to determinethe vertical position of the patient (symbol) in relation to the centretarget. Heart performance depends on rate, rhythm, inotropy, lusitropyin addition to mechanical impediments to the heart performance. If theheart performance E_(H)≦0.3, a check of mechanical factors from“outside-in” may be performed before assuming an inotropic orlusiotropic problems exists.

FIGS. 19 a-19 c illustrate various exemplary displays in accordance withcertain embodiments. Specifically, FIG. 19 a illustrates a display of apatient that may be slightly overfilled for the desired circulation. Inthis situation, volume loss, followed by arteriolar dilation may achievethe target circulation. In FIG. 19 b, the patient is well filled (P_(ms)is about 18.3) and the heart efficiency is 0.29. Exclusion of mechanicalimpediments to heart efficiency typically precede inotropes provideddiastolic dysfunction is not suspect. Arterial dilation generallyfollows. In FIG. 19 c, the patient is hypotensive and has a belowdesirable cardiac index. The display shows that the patient is wellfilled (P_(ms) is about 22 mmHg) but heart efficiency is only about 0.2.Depending on context, the patient may require an inotropic agent and/orechocardiography to help define the cause of the heart failure.

In certain embodiments, the P_(ms) measurement may be used to controlvenous return rather than the cardiac output as discussed above. Thisprocess helps define the volume state of the systemic circulation.Unlike a typical preload measure, P_(ms) has no dependence upon theheart or circulatory resistances. Measuring P_(ms) opens the possibilityof closed loop servo control of the volume state, e.g., in dialysis.P_(ms) further enables the measurement of E_(H) which, as discussedabove, defines the operation of the global heart and may be used as theobject of servo control for cardioactive agents. As detailed below, someof the value of E_(H) is volume recruitable if the patient is “volumeresponsive”—the remainder depends upon intrinsic properties of the heartand factors in the thorax local to the heart.

The notion of “volume responsiveness” has evolved over time because ithas been progressively realized that measures of the absolute value ofpreload (whichever is chosen) are poor or non-predictors of dynamic(MAP, CO etc) response to volume therapy.

Volume responsiveness is typically predicted by measuring systolicpressure variation, pulse pressure or pulse volume variation in patientson positive pressure ventilation. As the intrathoracic pressure risesand RAP rises the venous return (and CO) fall (discussed in more detailbelow). This effect may be ablated at higher values of P_(ms).Measurement of P_(ms) and Eh enables a quantitative approach to volumeresponsiveness. The maximum possible volume responsiveness may becalculated and the actual response measurable as a percent of themaximum. This may be a further use for P_(ms) in the quantitation ofcirculation definition and response to therapy. Therefore, in certainembodiments, by using P_(ms), measured circulatory variables may beresolved into their volumetric, resistive and cardiac parts. (e.g.,P_(ms) may be used in a range of derivatives for circulation control).

Generally, at a simple clinical level, the assessment of volume statecalls upon historical information (e.g., a history of fluid loss such asvomiting or diarrhoea) and the observation and assessment of a group ofsigns (e.g., increased heart rate, low blood pressure, low pulse volume,low venous pressure, low urine output, diminished sensorium, etc).Together, the history and examination may detect major volume statedisturbances. Where more sophisticated measurements are available,measures of the “preload” of the heart have historically formed a majorpart of the appreciation of the volume state. This is based onStarling's Law of the Heart (discussed above). These are direct orderived pressure or volume measures of the state of filling of theventricles of the heart during diastole. They include measures such asthe right atrial pressure (RAP), right and left end diastolicventricular pressures and volumes (RVEDP, LVEDP, RVEDV, LDEDV) togetherwith many other signals. Although preload may be defined in numerousways, it is clear that preload measures have resistance and heartdeterminants, in addition to volume determinants but are not true volumemeasures.

Low blood pressure and flow will result from a heart that does notcontract vigorously (inotropic disorder). A similar clinical picturewill result from a heart that contracts well but relaxes poorly duringdiastole. In this case the heart will not fill and there will thereforebe less blood to pump in the following systole (lusitropic disorder).This disorder is sometimes called diastolic dysfunction.

Bedside distinction of these two different states can be difficult.Inotropic problems are treated with an inotropic drug which increasesthe vigour of systolic contraction of the heart (e.g., adrenaline).Lusitropic disorders are treated by filling the heart to a higher volumestate, i.e., they are “volume responsive” (see below). They may also betreated with drugs.

As discussed above, P_(ms) is the steady state pressure in thecirculation when the heart is stopped. In many mammals, includinghumans, this static pressure is normally about 7 mmHg. P_(ms) may bemeasured using, for example, formula (1) above. P_(ms), which maynormally be controlled by the kidney together with water and sodiumintake, is a major determinant of the venous return to the heart.Starling's Law ensures that the cardiac output is servo controlled tothe systemic venous return VR_(s),

$\begin{matrix}{{VR}_{s} = {\frac{P_{m\; s} - {RAP}}{RVR}.}} & (24)\end{matrix}$

where RVR is resistance to venous return, determined significantly bytissue oxygen flow and metabolites together with neural and endocrinecontrol.

As also discussed above, variable E_(H) is an extremely useful measureof the global performance state of the heart, determined in turn byrate, rhythm, inotropy, lusitropy, etc. The systemic vascular resistance(SVR) is a measure of the relationship between blood pressure and flow(cardiac output) analogous to Ohm's Law and may be defined as,

$\begin{matrix}{{SVR} = \frac{{MAP} - {RAP}}{CO}} & (25)\end{matrix}$

As discussed above, the new derived measures of P_(ms) and E_(H)together with the systemic vascular resistance (SVR) may be combined tocontinually display the position of the patient in relation to the threeprime therapeutic dimensions, the volume, resistance and heart statesand other variables, such as oxygen delivery and venous oxygen invarious graphical realizations. This instrument allows the targeting ofa desired mean arterial pressure range and cardiac output or oxygendelivery range, which together define a control target area. Asdiscussed earlier, in certain embodiments the horizontal axis of thisinstrument may have one scale, the systemic vascular resistance scale(SVR) and the vertical axis may have two scales on the y-dimension, theP_(ms) scale and the E_(H) scale. This is because, although thecirculation control problem is three-dimensional, increase in bothP_(ms) and E_(H) increase MAP and CO. The 2^(nd) vertical scale E_(H)can be plotted next to P_(ms) for the current RAP given equation (3). Inan exemplary device, the patient's position may be shown as a solidcircle enclosed in an arrow (or “compass”). This arrow shows thepreferred next direction of therapy needed to achieve the targetcirculation. There are other 2-D and 3-D visual graphicalrepresentations that may be used as discussed above.

A practical clinical issue is not infrequently whether to increase MAPand/or CO by giving more fluid and increasing P_(ms) (with the attendantrisk of oedema and especially pulmonary oedema) or to start an inotropicor chronotropic drug like adrenaline which, in increasing the force andrate of the heart will increase E_(H), MAP and CO. Neither approach iswithout risk.

In contemplation of giving volume and increasing P_(ms), one may beinterested to know in advance whether the patient is “volumeresponsive”, i.e., whether MAP and CO will increase significantly for asmall rise in P_(ms) or the contrary. P_(ms) increases withadministration of volume.

Consideration of equation (1) shows that an increase of P_(ms) could bevariously partitioned between RAP, MAP and CO. This partitioning dependson how effectively the heart is beating and the circulatory resistances.Note that it is both MAP and CO that are of interest here. If RAPincreased alone, but without change in MAP or CO, no additional poweroutput would be achieved and the patient would thus not be “volumeresponsive”.

If MAP or CO or both increase, then more power is being delivered andpatient is volume responsive. We are thus interested in the power outputW delivered by the heart to the circulation. Accordingly, it is thepower responsiveness that is of interest in volume responsiveness (e.g.,changes in response to changes of P_(ms)). W may be given by:

W=CO(MAP−RAP)  (26)

Through mathematical derivation, W may be expressed in terms of P_(ms),

$\begin{matrix}{W = \frac{P_{m\; s}^{2}E_{H}^{2}{SVR}}{{RVR}^{2}}} & (27)\end{matrix}$

Volume responsiveness (α) may be measured as the sensitivity of W toP_(ms) changes, i.e., the partial derivative,

$\begin{matrix}{\alpha = {\frac{\partial W}{\partial P_{m\; s}} = {\frac{2W}{\left( {P_{m\; s} - {RAP}} \right)}\left( {1 - \frac{\partial{RAP}}{\partial P_{m\; s}}} \right)}}} & (28)\end{matrix}$

This expression for a allows appreciation of the anticipated power rise(mmHg·L/min) when the volume state (P_(ms)) is increased by 1 mmHg,i.e., the volume responsiveness. The maximum volume responsiveness, atthe current operating position, may be given by:

$\begin{matrix}{\alpha_{M\; {ax}} = \frac{2W}{\left( {P_{m\; s} - {RAP}} \right)}} & (29)\end{matrix}$

The actual volume responsiveness (α) can be indexed (α_(I)) by divisionby the patient's body surface area; or normalized by division by itsmaximum value (α_(N)). In the latter case,

$\begin{matrix}{\alpha_{N} = {\frac{\alpha}{\alpha_{M\; {ax}}} = \left( {1 - \frac{\partial{RAP}}{\partial P_{m\; s}}} \right)}} & (30)\end{matrix}$

Volume responsiveness may diminish with volume administration, forexample when RAP and P_(ms) increase faster than MAP and CO. If volumeresponsiveness is low but increases with volume administration, this mayindicate that the heart exhibits a lusitropic disorder.

The measures of volume responsiveness may be variously incorporated intoinstruments or systems for circulatory guidance and control.

The principles laid out above may be applied to manufacturing a softwarebased device to assist in circulatory care in mammalian patients. Thedevice may be similar to the device described above with respect to FIG.4. As discussed above, the purpose of the Circulatory Guidance System isto assist clinical users in targeting, assessing and managing thecirculatory system of patients in critical care. It does this byacquiring data in real time from bedside monitors, allowing the user toenter other patient parameters and desired or target circulatory values,computing derived variables and displaying these in a visual controlchart. The benefit of the system is the improved control of thecirculatory state and reduction of side effects associated with poorcontrol.

The circulatory guidance system interfaces to the bedside monitor andcardiac output monitor through standard physical connections serial ornetworked, wired or wireless. The Data Acquisition Module communicateswith the bedside device according to their specific and publishedcommunications protocols to request and receive data at defined rates. Apractical sampling rate is about 5 seconds. Typically measurements ofMAP and RAP are available from the standard beside monitor. Cardiacoutput CO is sometimes available from the bedside monitor and sometimesfrom dedicated devices. The Data Pre-Processing Module receives raw datafrom the Data Acquisition Module and performs range checking, artifactrejection and filtering to reduce signal noise. The Computation ofDerived Variables module performs a series of computations based on theprinciples. These are outlined in more detail below.

The Graphical Display and User Interaction Module allow the user toenter anthropometric and target data, and to see the numerical values ofkey variables. It displays a graphical chart showing the patient'sactual and desired state on P_(ms), SVR axes and also showing a dynamicE_(H) axis alongside the P_(ms) axis. The optimal tactical trajectory isshown as an arrow.

The various software modules can reside on the same hardware, running ageneral purpose or embedded operating system. A flexible arrangement isfor the Data Acquisition Module to be a server and for it to communicatewith the other modules using IP protocols and XML. This enables the DataAcquisition Module to be deployed on separate hardware as a dedicatedunit deployed close to the bedside monitors.

FIG. 20 shows the main elements of the software algorithm that controlsthe Circulatory Guidance System. In Step 1, the user can enteranthropometric and other data required by the algorithms, including age(A, years), height (H, cm) and weight (W, kg). In Step 2, computationsare made of body surface area (BSA, m²), the typical cardiac index forthe patient's age (CI_((A)), L/min/m²) and the corresponding cardiacoutput (CO_((A))L/min) as in equations (18)-(20) above. The age-adjustednorm mean arterial pressure (MAP_((A))) is determined by equation (21)above and the coefficients may be the same as described with respect toEquation (21). In Step 3, the user can set the desired target values formean arterial pressure (MAP) and cardiac output (CO). It is useful inpractice to be able to enter these values as upper and lower values,which contain a “target zone”. In Step 4, data are requested andreceived from the connected devices via the Data Acquisition Module. Atthis step, the data are pre-processed as described above. The raw datamay be displayed in numeric format on the display screen. A statusindicator can show whether data have been received on time, whetherthere are disconnections, range errors and so forth. In Step 5, variousderived variables are computed for the actual patient state (denoted by“Act”), namely the mean systemic filling pressure and systemic vascularresistance as defined by equations (22) and (23) above. Note that theseare best computed using the filtered or smoothed values of raw dataafter artifact rejection.

A chart in the form of FIG. 1 is displayed on the display screen. Thepatient's position is defined by equations (22) and (23). The directionof the optimal therapeutic trajectory is displayed as an arrow andcomputed using methods previously described. A zone representing thetarget range for MAP and CO is displayed by computing and graphing theisograms corresponding to the upper and lower target values of bothvariables using methods previously described. A convenient arrangementof the graphical chart is to position the mean target at the centre ofthe chart.

In practice, the chart is re-drawn with each new data receipt. Both theaxes and patient position move. An effective way is for the axes toslide on the display, giving the impression of a virtual instrument. TheE_(H) scale is plotted alongside the P_(ms) scale consistent withequation (3) using the current actual value of RAP. Over time, thiscreates the effect of the 2 scales moving relative to each other. Valuesof E_(H) below a threshold (usually 0.3) may be indicated by differentlycolored scale labels. If the patient's E_(H) is low an advisory messagemay be generated explaining potential causes and suggesting appropriateinvestigations and treatment.

The current volume responsiveness index of the patient's circulation maybe computed using,

$\begin{matrix}\left. {\alpha_{Act} = {\frac{2W_{Act}}{\left( {P_{msAct} - {RAP}_{Act}} \right)}\left( {1 - \frac{\partial{RAP}}{\partial P_{m\; s}}} \right._{Act}}} \right) & (31)\end{matrix}$

W_(Act) may be computed using

W _(Act)=(MAP_(Act)−RAP_(Act))CO_(Act)  (32)

In equation (31) an estimate needs to be made of δRAP/δP_(ms). A methodto do this is as follows: observe and record P_(ms) and RAP over aperiod of minutes (typically 5-8 min). Test for a systemic rise (orfall) of P_(ms) over the period of a minimum amount (typically 1-2mmHg)-ΔP_(ms). If there has been a systemic rise of P_(ms), the retrievethe corresponding change in RAP-ΔRAP. Estimate δRAP/δP_(ms) asΔRAP/ΔP_(ms).

In the presence of significant noise it is advisable to apply a furtherfilter to the P_(ms) and RAP data. Typically a median filter with a 5min. window is suitable.

There are a variety of methods to output the volume responsivenessresults. The choice of variables is threefold, and in some circumstancesit is helpful to have all three: Absolute volume responsiveness α_(Act);Volume responsiveness indexed by body surface area α_(I)=α_(Act)/BSA;and Volume responsiveness normalized by the maximum possible volumeresponsiveness at the current operating point α_(N)=α_(Act)/α_(Max).These results may be displayed as labeled numeric fields or as graphicalcharts. There are a range of possible graphical charts including:

1. On a 1-dimensional scale—this helps visualize the current value inrelation to reference points (such as α_(Max));

2. As time series—this is useful in showing trends;

3. A relational chart of heart performance E_(H) versus mean systemicfilling pressure P_(ms). An example of such a chart is depicted in FIG.21. Over time, the patient's position moves as a trajectory over thischart. Consider a patient at A. If they move to point B, then theincrease in P_(ms) is directed to RAP, and the patient has zero volumeresponsiveness. Point C is on the constant RAP line and corresponds tomaximum volume responsiveness. Point D is the general case where theslope of the line AD corresponds to tan θ as described above; and

4. A relational chart of power W versus mean systemic filling pressureP_(ms). An example of such a chart is depicted in FIG. 22. Over time,the patient's position moves as a trajectory over this chart. The slopeof the trajectory is the current value of the patient's absolute volumeresponsiveness α_(Act). Consider a patient at A moving to point B with aparticular slope and α_(Act). Sometime later they move from C to D witha lesser slope. This is analogous to the Starling curve, where increaseof heart output reduces as driving pressure increases. An innovation isthe ability to trace a Starling type response for a patient. This isenabled by using mean systemic pressure. Another patient at E has asimilar mean systemic pressure to the patient at A. However, thispatient does not respond with the same slope, and is much less volumeresponsive.

Below, various volume responsiveness scenarios and general examples ofcertain embodiments will be described.

Zero Volume Responsiveness

In the case that there is zero volume responsiveness, P_(ms)−RAP=const,and

$\begin{matrix}{\left( {1 - \frac{\partial{RAP}}{\partial P_{m\; s}}} \right) = {\left. 0\Rightarrow\alpha \right. = 0}} & (33)\end{matrix}$

Conceptually, in this case, the change in volume state P_(ms) isreflected in RAP change. None of the increased volume state changes COor MAP.

In the case of E_(H) being constant with P_(ms) changes:

$\begin{matrix}{\frac{\partial{RAP}}{\partial P_{{m\; s}\;}} = \frac{RAP}{P_{m\; s}}} & (34)\end{matrix}$

In this case the volume responsiveness becomes

$\begin{matrix}{\alpha = \frac{2W}{P_{m\; s}}} & (35)\end{matrix}$

For Maximal Volume Responsiveness, a patient can be said to be“maximally volume responsive” when the volume state P_(ms) change goesto CO or MAP change, and none to RAP change. The heart is capable ofdelivering the added volume state into pressure or flow. In this case,

$\begin{matrix}{{\frac{\partial{RAP}}{\partial P_{m\; s}} = {0\mspace{14mu} {and}}};{hence}} & (36) \\{\alpha_{M\; {ax}} = {\frac{2W}{\left( {P_{m\; s} - {RAP}} \right)}.}} & (37)\end{matrix}$

Volume responsiveness may be indexed to the patient's body surface area(α_(I)=α/BSA) or to the maximal volume responsiveness (α_(I)=α/α_(Max)).In the latter case, it follows that

$\begin{matrix}{\alpha_{N} = {\frac{\alpha}{\alpha_{M\; {ax}}} = {\left( {1 - \frac{\partial{RAP}}{\partial P_{m\; s}}} \right).}}} & (38)\end{matrix}$

In a practical system, it is useful to compute and display E_(H) and toobserve how it changes with P_(ms). The local slope is defined as:

$\begin{matrix}{{\tan \; \theta} = \frac{\Delta \; E_{H}}{\Delta \; P_{m\; s}}} & (39)\end{matrix}$

This may be easier to estimate than δRAP/δP_(ms), which is moresensitive to measurement noise. The general form (A12) becomes”

$\begin{matrix}{\alpha = {\frac{2W}{\left( {P_{m\; s} - {RAP}} \right)}\left\lbrack {1 - \left( {\frac{RAP}{P_{m\; s}} - {P_{m\; s}\tan \; \theta}} \right)} \right\rbrack}} & (40)\end{matrix}$

As discussed above, in determining the target cardiac output (CO), theclinician may use values chosen from experience or based on thepatient's age, height, weight and metabolic state. However, in certainembodiments, if the arterial oxygen saturation S_(a)O₂ is known (e.g.,from an oximeter finger clip) and arterial oxygen content is calculated,such as based on the following equation:

C_(a)O₂=Hb×1.34×S_(a)O₂  (41)

The oxygen delivery=(CO×C_(a)O₂) or oxygen delivery index=CI×C_(a)O₂ maybe displayed for the target CO and used to target the required CO.

Alternately, if the S_(a)O₂, S_(v)O₂ and CO are known, the CO target toachieve a certain {dot over (V)}O₂, (S_(v)O_(2desired)) may bedetermined based on the following equation:

{dot over (V)}O═CO(C_(a)O₂−C_(v)O₂)  (42)

and assuming in the first instance that the {dot over (V)}O₂ remainsconstant, the cardiac output required to achieve an S_(v)O_(2desired)may be given by:

$\begin{matrix}{{CO}_{desired} = \frac{\overset{.}{V}O_{2}}{\left( {{C_{a}O_{2}} - {C_{v}O_{2{desired}}}} \right)}} & (43)\end{matrix}$

In certain embodiments, as CO increases, this approach may be usediteratively to attain the desired CO for a target S_(v)O₂.

More specifically, the venous oxygen (S_(v)O₂) is a measure of theoxygen “left over” after the body has consumed ({dot over (V)}O₂, oxygenconsumption) what has been delivered (CO.C_(a)O₂, oxygen delivery). Alow S_(v)O₂ generally calls for a higher cardiac output. This may assistmonitor described herein with cardiac output targeting by “forwardestimating” the cardiac output for a particular S_(v)O₂, C_(v)O₂, a formof targeting.

The S_(cv)O₂ can be measured using right atrial catheters and isdifferent in value typically from the mixed venous saturation S_(mv)O₂measured using fibre optic pulmonary artery catheters. Both signals aregenerally continuous and may be measured using the Vigileo (S_(cv)O₂),and Vigilance (S_(mv)O₂). The venous oxygen is a measure of the balancebetween oxygen delivery DO₂=CO(C_(a)O₂) and oxygen consumption {dot over(V)}O₂=CO(C_(a)O₂−C_(v)O₂).

Measuring the venous oxygen is a mainstay of the oxygen economy allowingassessment of the sensitivity of the oxygen consumption to changes inoxygen delivery. Especially, one can assess if oxygen consumption issupply dependent, enabling better assessment of the wisdom of increasingcardiac output as a strategy to improve tissue oxygenation.

Measurement of S_(v)O₂ (S_(cv)O₂ or S_(mv)O₂) without knowledge of {dotover (V)}O₂ may, in certain embodiments, be misleading in situations ofdisordered circulation (e.g. sepsis) where regional maldistribution offlow may decrease {dot over (V)}O₂ and increase S_(v)O₂. When S_(v)O₂ ismeasured one should know the cardiac output and S_(a)O₂. In the absenceof such knowledge, outcome may be improved in sepsis by manipulatingcardiac output on the basis of the S_(cv)O₂.

In certain embodiments, the place of S_(v)O₂ (S_(cv)O₂, S_(mv)O₂) incirculation control may be consolidated by integrating S_(a)O₂ andS_(v)O₂ data into the determination of the target cardiac output.Knowledge of CO and S_(a)O₂, C_(a)O₂ may be used to measure oxygendelivery and the CO increase required to attain a desired DO₂ or DO₂I.Knowledge of CO, C_(a)O₂, C_(v)O₂ enables estimation of {dot over (V)}O₂using equations (41) and (42).

Assuming that {dot over (V)}O₂ remains constant the CO increase requiredto achieve a target S_(v)O_(2desired/)C_(v)O_(2desired) may becalculated using equation (43).

Certain embodiments may produce the following exemplary results.

Example 1

An 18 year old female patient, 2 days after fixation of thoraco-lumbarspine, and with a history of vomiting, with copious quantities of brightred blood. On examination, she was mentally obtunded, extremely pale,anxious, had a heart rate of 180. Her peripheral circulation was veryshutdown and she was sweating. The most likely diagnosis is a gastriculcer or Mallory-Weiss tear.

The initial solution is shown in FIG. 23 which shows a low cardiacoutput and blood pressure in the setting of a very low mean systemicfilling pressure (P_(ms)). The normal value of P_(ms) is 7 mmHg. This isthe pattern of profound hypovolemia. Sometimes the mean arterialpressure (MAP) is better preserved in young people than is the casehere.

Example 2

A 25 year old female patient that is prima gravida (first child), 26weeks pregnant. She has a history of hypertension of pregnancy. Admittedto hospital at 22 weeks and placed on a range of anti-hypertensivetherapies. The therapy failed to control the hypertension. She wasadmitted to the ICU after 4 weeks in the obstetric unit for the controlof hypertension with sodium nitroprusside as a prelude to delivery of a26 week pregnancy. The screen shot in FIG. 24 reveals that both meanarterial pressure and cardiac output are abnormally high, even forpregnancy. The P_(ms) of 19 mmHg suggests strongly that the hypertensionwas secondary to being over-filled. The patient was treated withdiuretics, had an excellent diuresis and the mean blood pressure fell to110 mmHg and the cardiac output to 8.3 L/min (see, FIG. 25). No deliverywas necessary to control hypertension.

Example 3

The patient is an 82 year old male, who had elective open heart surgery.Two hours post-operatively the patient became hypotensive and themeasured cardiac index fell to 1.3 L/min/m². The right atrial pressurerose to 18 mmHg. On the screen shot illustrated in FIG. 26, the P_(ms)rose to 22 mmHg and the heart performance E_(H) fell to 0.17.

In such a situation, mechanical causes of heart failure may beconsidered. In this patient, the right atrial pressure and pulmonaryartery mean pressure became equal, meaning that the right ventricle wasno longer doing the required work. A pericardial tamponade was relievedwith urgent thoracotomy and the patient did well. When E_(H)≦0.25 it isoften a good idea to do a trans thoracic echocardiograph.

Example 4

The patient is a 65 year old woman following emergency aortic aneurysmrepair. There was a history of pre-operative abdominal pain anddistension. The patient was anuric. Laparotomy revealed a rupturedinfra-renal aortic aneurysm. The screen in FIG. 27 shows the patient'ssituation on return to the ICU. The patient is both hypovolemic andarterially vasoconstricted. The patient compass is suggesting fluidtherapy before the institution of vasodilators. The next screen (FIG.28) shows the situation following the administration of volume therapy.The mean systemic pressure (P_(ms)), mean arterial pressure (MAP) andcardiac output (CO) have all risen. The compass now suggests that thepatient be arterially dilated in order to improve the cardiac index andoxygen delivery so that the patient may be within the target region asshown in FIG. 29.

Certain embodiments of methods, systems, devices and computer programproducts are disclosed that provide, among other things, therapeuticguidance for controlling a subject's circulation. Certain embodimentsenable a clinician or medical practitioner to monitor circulation in apatient and advantageously assist in therapeutic maintenance of subjectcirculatory dynamics. Embodiments of the present inventions areapplicable to mammalian subjects other than human beings, including, butnot limited to, domestic animals such as dogs, cats and horses. Thecoefficients in certain of the equations described hereinbefore may bechanged to reflect different sizes, and age-adjusted normal values indifferent animals.

Example 5

A study was conducted to evaluate the safety and efficacy of a guidancesystem in accordance with certain embodiments. The study's objective wasto demonstrate that the use of this guidance system safely provides theclinician with appropriate data and guidance to better achieve andmaintain tighter haemodynamic stability when compared to conventionalcare. Haemodynamic stability was measured by a patient's closeness to atarget mean arterial pressure (MAP) and cardiac output or index (CO, CI)as prescribed by the physician. A target region around the targets wasdefined by upper and lower boundaries. This study was a multi-centre,prospective, randomized controlled trial conducted in 7 Australiantertiary ICUs. The patient population comprised 112 patients recoveringin ICU following surgery consisting of coronary bypass grafting and/orheart valve repair or replacement, using cardio-pulmonary bypass.

Method:

The version of Navigator™ used was a free-standing touch-panel monitorthat integrates with bedside multi-parameter and hemodynamic monitors.The Navigator™ version used in this study continuously acquires datafrom the bedside monitors every few seconds. The data includes meanarterial pressure (MAP), right atrial pressure (RAP), cardiac output andindex (CO, CI) and arterial and venous oxygen saturations (SaO2, SvO2).Other data such as patient age, height, weight and hemoglobin aremanually entered into the system by the user. The physician specifiesthe prescribed circulation (the “target” circulation) by entering meanvalues or ranges for MAP, CO or CI and/or oxygen delivery index (ODI).The Navigator computes estimates of mean systemic filling pressure(Pms—a measure of volume state), heart performance (Eh) and aconventional measure of systemic vascular resistance (SVR). Thepatient's current state and target state are charted on a display, whichshows the therapeutic change needed to take the patient into the targetzone. The axes of the display correspond to volume (or diuretic),vasoactive and cardioactive therapies. A guidance arrow advises on nextappropriate therapy. The display is updated every few seconds andprovides 24 h continuous support to the bedside nurse and physician, asthe patient's state changes in response to disease process or therapy.The goals of hemodynamic therapy are specified for the clinical team, aswell as progress in achieving them. Patients were randomized toNavigator-supported clinician care or to conventional clinician care onadmission to the ICU. Although data on MAP and CO were continuouslylogged in both arms only those patients randomized to the treatment(Navigator) arm had the benefit of the Navigator graphical interfaceshowing continually the patient position in relation to the targets set.In the control arm the Navigator graphical display was blacked out. Theprimary endpoint was a measure of how well both MAP and CO werestabilized to the centre of this target region, whilst connected toNavigator. The average standardized distance or ASD in this study wasdefined as follows: the 2 variables being controlled, MAP and CO, werecombined in a normed Euclidean distance measure, scaled by therespective widths of their target regions. This is referred to as the“average standardized distance” or ASD.

Number of Subjects:

According to the protocol sufficient patients were to be consented toallow 100 patients to complete the study (50 in each treatment arm). Atotal of 112 patients were enrolled into the study and formed the intentto treat population. Of these 105 patients completed the study asplanned and formed the modified intent to treat (MITT) population (57patients in the Navigator™ arm and 48 patients in the control arm).Patient demographics (see Table 1), enrolment status (see Table 2) andsurgical procedures (see Table 3) were matched between the Navigator andcontrol arms.

TABLE 1 Summary of Subject Demography NAV-1 Control Total (N = 59) (N =53) (N = 112) AGE N 59 53 112 (YEARS) MEAN (SD) 61 (12)   67 (11)   64(12)   MEDIAN 63 67  64 MIN, MAX 31, 85 45, 90 31, 90 SEX MALE 45 (76.3)35 (66.0) 80 (71.4) FEMALE 14 (23.7) 18 (34.0) 32 (28.6) RACE CAUCASIAN38 (64.4) 38 (71.7) 76 (67.9) ASIAN 3 (5.1) 0 (0.0) 3 (2.7)AFRICAN-AMERICAN 1 (1.7) 0 (0.0) 1 (0.9) HISPANIC 0 (0.0) 1 (1.9) 1(0.9) OTHER  8 (13.6)  6 (11.3) 14 (12.5) NOT COLLECTED  9 (15.3)  8(15.1) 17 (15.2) HEIGHT N 59 53 112 (CM) MEAN (SD) 170.57 (8.975)  167.19 (8.961)   168.97 (9.088)   MEDIAN   170.00   168.00   169.50 MIN,MAX 150.0, 189.0 149.0, 188.0 149.0, 189.0 WEIGHT N 59 53 112 (KG) MEAN(SD) 85.32 (17.986)  79.60 (16.219)  82.61 (17.335)  MEDIAN   84.60  79.40   82.30 MIN, MAX  53.0, 140.0  40.6, 120.6  40.6, 140.0

TABLE 2 Summary of Enrolment, Status and Disposition NAV-1 Control Total(N = 59) (N = 53) (N = 112) INTENT-TO-TREAT  59 (100.0)  53 (100.0) 112(100.0) POPULATION COMPLETED STUDY 57 (96.6) 50 (94.3) 107 (95.5)  ASPLANNED WITHDREW FROM STUDY 2 (3.4) 3 (5.7) 5 (4.5) REASONS FORWITHDRAWAL: ADVERSE EVENT 1 (1.7) 0 (0.0) 1 (0.9) PATIENT 0 (0.0) 0(0.0) 0 (0.0) NON-COMPLIANCE PATIENT REQUEST 0 (0.0) 0 (0.0) 0 (0.0)INVESTIGATOR OR 0 (0.0) 0 (0.0) 0 (0.0) SPONSOR REQUEST TERMINATION OFTHE 0 (0.0) 0 (0.0) 0 (0.0) STUDY BY THE SPONSOR PROTOCOL VIOLATION 0(0.0) 1 (1.9) 1 (0.9) THE PATILENT DIED 1 (1.7) 0 (0.0) 1 (0.9) LOST TOFOLLOW-UP 0 (0.0) 0 (0.0) 0 (0.0) OTHER 0 (0.0) 2 (3.8) 2 (1.8)

TABLE 3 Summary of Baseline Characteristics NAV-1 Control Total TYPE OFSURGERY: (N = 59) (N = 53) (N = 112) CORONARY ARTERY BYPASS 46 (78.0) 42(79.2) 88 (78.6) GRAFTING VALVULAR REPAIR 2 (3.4) 3 (5.7) 5 (4.5) MITRALVALVE 5 (8.5) 3 (5.7) 8 (7.1) PROSTHESIS INSERTED: RING 0 (0.0) 2 (3.8)2 (1.8) PROSTHESIS INSERTED: VALVE 13 (22.0) 13 (24.5) 26 (23.2)VALVULAR REPLACEMENT 14 (23.7) 13 (24.5) 27 (24.1) AORTIC VALVE 14(23.7) 18 (34.0) 32 (28.6) OTHER 2 (3.4) 3 (5.7) 5 (4.5) DURATION OFSURGERY (MINS) N 58 52 110 MEAN 263 (74)   243 (74)   254 (75)   (SD)MEDIAN 255  230  248 MIN, 115, 420 135, 526 115, 526 MAX DURATION ONNAVIGATOR N 59 51 110 (HOURS) MEAN 26.19 (19.255) 20.16 (13.890) 23.39(17.174) (SD) MEDIAN   20.09   18.56    19.70 MIN,  0.4, 116.4  0.1,76.6  0.1, 116.4 MAX DURATION IN ICU (HOURS) N 57 45 102 — MEAN 53.01(30.742) 51.20 (30.052) 52.21 (30.303) (SD) MEDIAN   46.50   45.07   46.13 MIN,  18.2, 160.3  12.8, 146.5  12.8, 160.3 MAX DURATION INHOSPITAL N 52 47  99 (HOURS) MEAN 217.72 (126.683) 258.91 (205.500)237.28 (169.120) (SD) MEDIAN   173.32   188.67   177.42 MIN, 116.3,702.1  117.0, 1012.0  116.3, 1012.0 MAX

Primary Endpoint Results:

The ASD in Navigator patients was 1.71 vs. Control 1.92, for allpatients, all centres and all time connected to Navigator. The lesservalue represents improved haemodynamic stability with Navigator, —abenefit of 10.9% (see FIG. 37). The t-test of difference in means gave ap-value of 0.202 with the 95% CI of the difference, −5.7% worse to 27.1%better for Navigator compared to control. Note that ASD is the averagecontrol over the entire period for which the Navigator was connected.

We concluded that a Navigator-supported clinician achieves haemodynamicstability with the same or better performance than an unsupportedclinician (non-inferiority conclusion). There was a strong trend towardssuperiority for Navigator. The ASD measure does not have an intuitiveinterpretation. Further, there is an “area” effect—the area enclosed bythe ASD is proportional to the square of the ASD, yet we compared theradial changes.

The secondary endpoint of time in target zone is easier to understandand interpret clinically. There was an increase in percentage of time inthe target zone from control 32.4% to Navigator 38.4% (p=0.116), anabsolute increase of 6.0% with 95% confidence interval −1.5% decrease toa 13.5% increase. The absolute increase of 6% corresponds to a relativeincrease of 18.5%. The benefit judged this way is substantially greaterthan with ASD. The ASD and % time in target zone were also analyzed foreach 1 hour block of care, as shown in FIGS. 38 and 39.

By the third hour after ICU admission, Navigator patients were in thetarget zone 44% of the time, compared with 30% in the control group(p=0.047). Navigator patients were maintained better at target levels.Over the subsequent 8 hours of care, Navigator patients were in target40% of the time, and control patients 33% of the time. Post hoc analysisshowed that there was a significant effect of ICU centre on mean ASD.There was greater heterogeneity than anticipated in both control levelsand Navigator effect amongst centres. For example, the control level ofASD varied from 1.26 to 2.44 between centres. We examined this effectwith ANOVA using treatment arm and centre as variables. ANOVAs wereperformed on ASD and % time in target zone over the first 12 hours ofcare. There is a trend significance in the treatment effect for both ASDand % time in target zone (see Table 4 below).

TABLE 4 Source Type III Sum df Mean Squ

 F Sig. % time in Treat 14753.563 1 14753.56 3.461 0.066 window Centre79869.904 5 15973.98 3.757 0.004 Std Dist. Treat 18.245 1 18.245 3.2480.075 Centre 129.556 5 25.911 4.625 0.001

indicates data missing or illegible when filed

Secondary Efficacy Endpoints:

There was an increase in percentage of time in the target zone fromcontrol 32.4% to Navigator 38.4% (p=0.116), over all patients andcentres (not correcting for centre control heterogeneity). Incidence ofAF whilst connected to Navigator was low, (Navigator 5.3%, Control 6.3%)and not significantly different. SOFA scores were not statisticallysignificantly different between the two treatment arms on Day 1 and Day2. There was a statistically significant difference between the twotreatment arms in terms of mean SOFA scores in favour of Navigator atDay 3. There were no serious adverse events classified as associatedwith Navigator. There were no device failures.

Other Results:

Total fluid intake, urine output and blood loss were similar betweenboth groups (Table 5). Table 6 shows a summary of patients who receivedone or more treatments with inotropes and vasoactives.

TABLE 5 Summary of Fluid Balance NAV-1 Control Total (N = 59) (N = 53)(N = 112) TOTAL FLUID INTAKE FOR N 58 50 108 THE TIME ON NAVIGATOR (ml)MEAN 4868.09 4523.80 4708.69 (SD) (3241.93) (2224.57) (2809.77) MEDIAN4131.00 4088.00 4088.00 MIN, 723.0, 19996.0  916.0, 10955.0 723.0,19996.0 MAX TOTAL URINE OUTPUT FOR N 58 50 108 THE TIME ON NAVIGATOR(ml) MEAN 2707.50 2428.08 2578.14 (SD) (1810.01) (1405.96) (1634.03)MEDIAN 2436.50 2052.50 2197.00 MIN,  15.0, 12030.0 420.0, 6402.0  15.0,12030.0 MAX TOTAL BLOOD LOSS FOR THE N 56 49 105 TIME ON NAVIGATOR (ml)MEAN 600.21 597.37 598.89 (SD) (368.468) (388.604) (376.166) MEDIAN510.00 475.00 500.00 MIN, 120.0, 2500.0  74.0, 2348.0 74.0, 2500.0 MAX

TABLE 6 Summary of Inotrope and Vasoactive Use (patients received atleast one treatment) NAV-1 Control Total (N = 59) (N = 53) (N = 112)DOBUTAMINE  8 (13.5)  8 (15.1) 16 (14.2) DOPAMINE 1 (1.7) 2 (3.8) 3(2.7) EPINEPHRINE 12 (20.3) 15 (28.3) 27 (24.1) GLYCERYL TRINITRATE 49(83.1) 49 (92.5) 98 (87.5) NITROPRUSSIDE SODIUM 16 (27.1) 11 (20.8) 27(24.1) NOREPINEPHRINE 41 (69.5) 34 (64.2) 75 (67.0)

CONCLUSIONS

This study was of an innovative critical care device for hemodynamicguidance. The study shows that 24 hour continuous beside circulationguidance is possible, effective and safe. It is surprising that acomputer guidance system can adjust to the complex, often chaotic,circulatory dynamics in this critically-ill patient group. Using the apriori end-point of average standardized distance (ASD), the studyshowed that Navigator was the same or better than conventional care inachieving circulatory control to physician-set targets, with a meanbenefit of a 10.9% reduction in ASD. The secondary endpoint of % time intarget zone was also a same or better result with an increase from 32.4%in the control group to 38.4% in the Navigator group, a relativeincrease of 18.5%. Patients managed with Navigator were resuscitatedmore quickly. By the third hour after ICU admission, Navigator patientswere in the target zone 44% of the time, compared with 30% in thecontrol group (p=0.047). Navigator patients were maintained better attarget levels. Over the subsequent 8 hours of care, Navigator patientswere in target 40% of the time, and control patients 33% of the time.There was strong centre heterogeneity. When results were corrected posthoc for this heterogeneity, there was a strong trend towardssuperiority. Levels of ASD (Navigator 1.71, Control 1.92) were higherthan that used in power calculations (1.30), which were based on datafrom the development centre. Thus the study may have been underpowered(though this was not detected at the interim analysis point). Data fromNAV-1 will be very helpful in powering future studies. The averagestandardized distance (ASD) measure is similar to measures of averagecontrol error used in process engineering. However, it is unfamiliar toclinicians and hard to interpret. We have found that the percentage timein target zone is more intuitive and lends itself to clinicalinterpretation. Further it corresponds closely to the intended use ofNavigator which is to help clinicians drive the circulation into thetarget zone. Cardiac surgery patients recovering in ICU are a welldefined group for recruitment into clinical studies. They also present awide range of unstable haemodynamic situations and range of therapeuticinterventions. However, there are other patient groups, such ashigh-risk surgery and sepsis, where outcomes benefits have beendemonstrated for goal-directed therapy (usually in oxygen deliveryterms). These patient groups may be appropriate for future Navigatorstudies. It will be appreciated that numerous variations and/ormodifications may be made to the embodiments disclosed without departingfrom the spirit or scope of the inventions as broadly described.

1. A computer-assisted method for assessing a subject's circulationstate, said method comprising at least one of the following steps: (i)determining said subject's present circulatory state using parameterssufficient to characterize the present circulatory state; and (ii)determining said subject's desired circulatory state using parameterssufficient to characterize the desired circulatory state.
 2. Thecomputer assisted method of claim 1, wherein the method is used forproviding a treatment guidance for said subject.
 3. The computerassisted method of claim 1, wherein the method is used to measure saidsubject's circulation state.
 4. The computer-assisted method of claim 2,wherein a target direction is determined of a trajectory from saidsubject's present circulatory state to said subject's desiredcirculatory state.
 5. The computer-assisted method of claim 4, whereinthe treatment guidance, the target direction and the trajectory are usedto assisted in moving said subject's circulatory state along towards adesired circulatory state.
 6. The computer-assisted method of claim 5,wherein the treatment guidance, the target direction and the trajectoryare used to assisted in providing treatment sequencing guidance in orderto move said subject's circulatory state along towards a desiredcirculatory state.
 7. The computer-assisted method of claim 1, whereinsaid subject's present state and/or said subject's desired state arevisually represented.
 8. The computer-assisted method of claim 1,wherein said subject's present circulatory state is determined as afunction of at least mean systemic filling pressure (P_(MS)), heartefficiency (E_(H)) and systemic vascular resistance (SVR).
 9. Thecomputer-assisted method of claim 1, wherein said subjects presentcirculatory state and/or desired circulatory is continually determined.10. The computer-assisted method of claim 1, wherein the method providessubstantially continuous and/or intermittent guidance of said subjectscirculatory state and/or control of hemodynamic and oxygen management ofsaid subject's circulatory system.
 11. The computer-assisted method ofclaim 1, wherein the method is used to provide substantially continuousand/or intermittent guidance of at least one of the following: fluidtherapies for control of volume state, heart performance therapy, heartrate therapies, heart rhythm therapies and/or vasoactive therapies.12.-31. (canceled)
 32. A computer-assisted method for assessing asubject's volume responsiveness state, said method comprising at leastone of the following steps: (i) determining said subject's presentvolume responsiveness state as a function of at least mean systemicfilling pressure (P_(ms)) and heart efficiency (E_(H)); and (ii)determining said subject's desired volume responsive state as a functionof at least mean systemic filling pressure (P_(ms)) and heart efficiency(E_(H)).
 33. The computer-assisted method of claim 32, wherein atreatment guidance, a target direction and a trajectory are used toassisted in providing treatment sequencing guidance in order to movesaid subject's volume responsiveness state along towards a desiredvolume responsiveness state.
 34. The computer-assisted method of claim32 wherein said subject's present state and/or said subject's desiredstate are visually represented.
 35. The computer-assisted method ofclaim 32, wherein said subjects present volume responsive state iscontinually determined.
 36. The computer-assisted method of claim 32,wherein the method provides substantially continuous and/or intermittentguidance of said subjects volume responsive state.
 37. Acomputer-assisted method for assessing at least one of a subject's powervolume responsiveness and cardiac output volume responsiveness, saidmethod comprising: (i) determining at least one of said subject'spresent power volume responsiveness and present cardiac output volumeresponsiveness using parameters sufficient to characterize at least oneof said subject's power volume responsiveness and cardiac output volumeresponsiveness; and (ii) determining at least one of said subject'sdesired power volume responsiveness and desired cardiac output volumeresponsiveness using parameters sufficient to characterize at least oneof said subject's power volume responsiveness and cardiac output volumeresponsiveness; wherein heart efficiency (E_(H)) is substantiallyconstant.
 38. The computer-assisted method of claim 37, wherein atreatment guidance, a target direction and a trajectory are used toassisted in moving at least one of said subject's present power volumeresponsiveness state and present cardiac output volume responsivenessstate along towards at least one of a desired power volumeresponsiveness state and a desired cardiac output volume responsivenessstate.
 39. The computer-assisted method of claim 37, wherein saidsubject's present state and/or said subject's desired state are visuallyrepresented.
 40. The computer-assisted method of claim 37, wherein atleast one of said subjects present power volume responsiveness state andpresent cardiac output volume responsiveness state and/or at least oneof said subjects desired power volume responsiveness state and desiredcardiac output volume responsiveness state is continually determined.41. The computer-assisted method of claim 37, wherein the methodprovides substantially continuous and/or intermittent guidance of atleast one of said subjects power volume responsiveness state and presentcardiac output volume responsiveness state.